Antiproliferative compounds and methods of use thereof

ABSTRACT

Compounds of formula I for treating, preventing or managing cancer are disclosed. Also disclosed are methods of treating, preventing or managing cancer, such as leukemia, comprising administering the compounds. In certain embodiments, the method of treatment comprise administering a compound provided herein in combination with a second agent. Pharmaceutical compositions and single unit dosage forms comprising the compounds are also disclosed.

1. CROSS REFERENCE TO RELATED APPLICATIONS

This application is continuation of U.S. application Ser. No.15/723,065, filed Oct. 2, 2017, which is a continuation of U.S.application Ser. No. 15/275,045, filed Sep. 23, 2016 issued as U.S. Pat.No. 9,808,451, which is a continuation of U.S. application Ser. No.14/795,837, filed Jul. 9, 2015 issued as U.S. Pat. No. 9,499,514, whichclaims the benefit of the priority of U.S. Provisional Application No.62/023,775, filed Jul. 11, 2014, the disclosures of each which is areincorporated herein by reference in their entireties.

2. FIELD

Provided herein are compounds for treating, preventing or managingcancer. Also provided are pharmaceutical compositions comprising thecompounds and methods of use of the compounds and compositions. Incertain embodiments, the methods encompass treating, preventing ormanaging cancer, including solid tumors and blood borne tumors using thecompounds provided herein.

3. BACKGROUND

Pathobiology of Cancer

Cancer is characterized primarily by an increase in the number ofabnormal cells derived from a given normal tissue, invasion of adjacenttissues by these abnormal cells, or lymphatic or blood-borne spread ofmalignant cells to regional lymph nodes and to distant sites(metastasis). Clinical data and molecular biologic studies indicate thatcancer is a multistep process that begins with minor preneoplasticchanges, which may under certain conditions progress to neoplasia. Theneoplastic lesion may evolve clonally and develop an increasing capacityfor invasion, growth, metastasis, and heterogeneity, especially underconditions in which the neoplastic cells escape the host's immunesurveillance. Roitt, I., Brostoff, J and Kale, D., Immunology,17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).

There is an enormous variety of cancers which are described in detail inthe medical literature. Examples include cancer of the lung, colon,rectum, prostate, breast, brain, and intestine. The incidence of cancercontinues to climb as the general population ages, as new cancersdevelop, and as susceptible populations (e.g., people infected with AIDSor excessively exposed to sunlight) grow. A tremendous demand thereforeexists for new methods and compositions that can be used to treatpatients with cancer.

Many types of cancers are associated with new blood vessel formation, aprocess known as angiogenesis. Several of the mechanisms involved intumor-induced angiogenesis have been elucidated. The most direct ofthese mechanisms is the secretion by the tumor cells of cytokines withangiogenic properties. Examples of these cytokines include acidic andbasic fibroblastic growth factor (a,b-FGF), angiogenin, vascularendothelial growth factor (VEGF), and TNF-α. Alternatively, tumor cellscan release angiogenic peptides through the production of proteases andthe subsequent breakdown of the extracellular matrix where somecytokines are stored (e.g., b-FGF). Angiogenesis can also be inducedindirectly through the recruitment of inflammatory cells (particularlymacrophages) and their subsequent release of angiogenic cytokines (e.g.,TNF-α, b-FGF).

Lymphoma refers to cancers that originate in the lymphatic system.Lymphoma is characterized by malignant neoplasms of lymphocytes-Blymphocytes and T lymphocytes (i.e., B-cells and T-cells). Lymphomagenerally starts in lymph nodes or collections of lymphatic tissue inorgans including, but not limited to, the stomach or intestines.Lymphoma may involve the marrow and the blood in some cases. Lymphomamay spread from one site to other parts of the body.

The treatment of various forms of lymphomas are described, for example,in U.S. Pat. No. 7,468,363, the entirety of which is incorporated hereinby reference. Such lymphomas include, but are not limited to, Hodgkin'slymphoma, non-Hodgkin's lymphoma, cutaneous B-cell lymphoma, activatedB-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle celllymphoma (MCL), follicular center lymphoma, transformed lymphoma,lymphocytic lymphoma of intermediate differentiation, intermediatelymphocytic lymphoma (ILL), diffuse poorly differentiated lymphocyticlymphoma (PDL), centrocytic lymphoma, diffuse small-cleaved celllymphoma (DSCCL), peripheral T-cell lymphomas (PTCL), cutaneous T-Celllymphoma and mantle zone lymphoma and low grade follicular lymphoma.

Non-Hodgkin's lymphoma (NHL) is the fifth most common cancer for bothmen and women in the United States, with an estimated 63,190 new casesand 18,660 deaths in 2007. Jemal A, et al., CA Cancer J Clin 2007;57(1):43-66. The probability of developing NHL increases with age andthe incidence of NHL in the elderly has been steadily increasing in thepast decade, causing concern with the aging trend of the US population.Id. Clarke C A, et al., Cancer 2002; 94(7):2015-2023.

Diffuse large B-cell lymphoma (DLBCL) accounts for approximatelyone-third of non-Hodgkin's lymphomas. While some DLBCL patients arecured with traditional chemotherapy, the remainder die from the disease.Anticancer drugs cause rapid and persistent depletion of lymphocytes,possibly by direct apoptosis induction in mature T and B cells. See K.Stahnke. et al., Blood 2001, 98:3066-3073. Absolute lymphocyte count(ALC) has been shown to be a prognostic factor in follicularnon-Hodgkin's lymphoma and recent results have suggested that ALC atdiagnosis is an important prognostic factor in diffuse large B-celllymphoma. See D. Kim et al., Journal of Clinical Oncology, 2007 ASCOAnnual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement),2007: 8082.

Leukemia refers to malignant neoplasms of the blood-forming tissues.Various forms of leukemias are described, for example, in U.S. Pat. No.7,393,862 and U.S. provisional patent application No. 60/380,842, filedMay 17, 2002, the entireties of which are incorporated herein byreference. Although viruses reportedly cause several forms of leukemiain animals, causes of leukemia in humans are to a large extent unknown.The Merck Manual, 944-952 (17^(th) ed. 1999). Transformation tomalignancy typically occurs in a single cell through two or more stepswith subsequent proliferation and clonal expansion. In some leukemias,specific chromosomal translocations have been identified with consistentleukemic cell morphology and special clinical features (e.g.,translocations of 9 and 22 in chronic myelocytic leukemia, and of 15 and17 in acute promyelocytic leukemia). Acute leukemias are predominantlyundifferentiated cell populations and chronic leukemias more mature cellforms.

Acute leukemias are divided into lymphoblastic (ALL) andnon-lymphoblastic (ANLL) types. The Merck Manual, 946-949 (17^(th) ed.1999). They may be further subdivided by their morphologic andcytochemical appearance according to the French-American-British (FAB)classification or according to their type and degree of differentiation.The use of specific B- and T-cell and myeloid-antigen monoclonalantibodies are most helpful for classification. ALL is predominantly achildhood disease which is established by laboratory findings and bonemarrow examination. ANLL, also known as acute myelogenous leukemia oracute myeloblastic leukemia (AML), occurs at all ages and is the morecommon acute leukemia among adults; it is the form usually associatedwith irradiation as a causative agent.

Chronic leukemias are described as being lymphocytic (CLL) or myelocytic(CML). The Merck Manual, 949-952 (17^(th) ed. 1999). CLL ischaracterized by the appearance of mature lymphocytes in blood, bonemarrow, and lymphoid organs. The hallmark of CLL is sustained, absolutelymphocytosis (>5,000/μL) and an increase of lymphocytes in the bonemarrow. Most CLL patients also have clonal expansion of lymphocytes withB-cell characteristics. CLL is a disease of middle or old age. In CML,the characteristic feature is the predominance of granulocytic cells ofall stages of differentiation in blood, bone marrow, liver, spleen, andother organs. In the symptomatic patient at diagnosis, the total whiteblood cell (WBC) count is usually about 200,000/μL, but may reach1,000,000/μL. CML is relatively easy to diagnose because of the presenceof the Philadelphia chromosome.

In addition to the acute and chronic categorization, neoplasms are alsocategorized based upon the cells giving rise to such disorder intoprecursor or peripheral. See e.g., U.S. patent publication no.2008/0051379, the disclosure of which is incorporated herein byreference in its entirety. Precursor neoplasms include ALLs andlymphoblastic lymphomas and occur in lymphocytes before they havedifferentiated into either a T- or B-cell. Peripheral neoplasms arethose that occur in lymphocytes that have differentiated into either T-or B-cells. Such peripheral neoplasms include, but are not limited to,B-cell CLL, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma,mantle cell lymphoma, follicular lymphoma, extranodal marginal zoneB-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginalzone lymphoma, splenic marginal zone lymphoma, hairy cell leukemia,plasmacytoma, diffuse large B-cell lymphoma and Burkitt lymphoma. Inover 95 percent of CLL cases, the clonal expansion is of a B celllineage. See Cancer: Principles & Practice of Oncology (3rd Edition)(1989) (pp. 1843-1847). In less than 5 percent of CLL cases, the tumorcells have a T-cell phenotype. Notwithstanding these classifications,however, the pathological impairment of normal hematopoiesis is thehallmark of all leukemias.

Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow.Normally, plasma cells produce antibodies and play a key role in immunefunction. However, uncontrolled growth of these cells leads to bone painand fractures, anemia, infections, and other complications. Multiplemyeloma is the second most common hematological malignancy, although theexact causes of multiple myeloma remain unknown. Multiple myeloma causeshigh levels of proteins in the blood, urine, and organs, including butnot limited to M-protein and other immunoglobulins (antibodies),albumin, and beta-2-microglobulin. M-protein, short for monoclonalprotein, also known as paraprotein, is a particularly abnormal proteinproduced by the myeloma plasma cells and can be found in the blood orurine of almost all patients with multiple myeloma.

Skeletal symptoms, including bone pain, are among the most clinicallysignificant symptoms of multiple myeloma. Malignant plasma cells releaseosteoclast stimulating factors (including IL-1, IL-6 and TNF) whichcause calcium to be leached from bones causing lytic lesions;hypercalcemia is another symptom. The osteoclast stimulating factors,also referred to as cytokines, may prevent apoptosis, or death ofmyeloma cells. Fifty percent of patients have radiologically detectablemyeloma-related skeletal lesions at diagnosis. Other common clinicalsymptoms for multiple myeloma include polyneuropathy, anemia,hyperviscosity, infections, and renal insufficiency.

Solid tumors are abnormal masses of tissue that may, but usually do notcontain cysts or liquid areas. Solid tumors may be benign (not cancer),or malignant (cancer). Different types of solid tumors are named for thetype of cells that form them. Examples of types solid tumors include,but are not limited to malignant melanoma, adrenal carcinoma, breastcarcinoma, renal cell cancer, carcinoma of the pancreas, non-small-celllung carcinoma (NSCLC) and carcinoma of unknown primary. Drugs commonlyadministered to patients with various types or stages of solid tumorsinclude, but are not limited to, celebrex, etoposide, cyclophosphamide,docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combinationthereof.

While patients who achieve a complete remission after initial therapyhave a good chance for cure, less than 10% of those who do not respondor relapse achieve a cure or a response lasting longer than 3 years. SeeCerny T, et al., Ann Oncol 2002; 13 Suppl 4:211-216.

Rituximab is known to deplete normal host B cells. See M. Aklilu et al.,Annals of Oncology 15:1109-1114, 2004. The long-term immunologic effectsof B cell depletion with rituximab and the characteristics of thereconstituting B cell pool in lymphoma patients are not well defined,despite the widespread usage of this therapy. See Jennifer H. Anolik etal., Clinical Immunology, vol. 122, issue 2, February 2007, pages139-145.

The approach for patients with relapsed or refractory disease reliesheavily on experimental treatments followed by stem celltransplantation, which may not be appropriate for patients with a poorperformance status or advanced age. Therefore, a tremendous demandexists for new methods that can be used to treat patients with NHL.

The link between cancer an altered cellular metabolism has been wellestablished. See Cairns, R. A., et al. Nature Rev., 2011, 11:85-95.Understanding tumor cell metabolism and the associated genetic changesthereof may lead to the identification of improved methods of cancertreatment. Id. For example, tumor cell survival and proliferation viaincreased glucose metabolism has been linked to the PIK3 pathway,whereby mutations in tumor suppressor genes such as PTEN activate tumorcell metabolism. Id. AKT1 (a.k.a., PKB) stimulates glucose metabolismassociated with tumor cell growth by various interactions with PFKFB3,ENTPD5, mTOR and TSC2 (a.k.a., tuberin). Id.

Transcription factors HIF1 and HIF2 are largely responsible for cellularresponse to low oxygen conditions often associated with tumors. Id. Onceactivated, HIF1 promotes tumor cell capacity to carry out glycolysis.Id. Thus, inhibition of HIF1 may slow or reverse tumor cell metabolism.Activation of HIF1 has been linked to PI3K, tumor suppressor proteinssuch as VHL, succinate dehydrogenase (SDH) and fumarate hydratase. Id.The oncogenic transcription factor MYC has also been linked to tumorcell metabolism, specifically glycolysis. Id. MYC also promotes cellproliferation by glutamine metabolic pathways. Id.

AMP-activated protein kinase (AMPK) functions as a metabolic check pointwhich tumor cells must overcome in order to proliferate. Id. Severalmutations have been identified which suppress AMPK signaling in tumorcells. See Shackelford, D. B. & Shaw, R. J., Nature Rev. Cancer, 2009,9: 563-575. STK11 has been identified as a tumor suppressor gene relatedto the role of AMPK. See Cairns, R. A., et al. Nature Rev., 2011,11:85-95.

The transcription factor p53, a tumor suppressor, also has an importantrole in the regulation of cellular metabolism. Id. The loss of p53 intumor cells may be a significant contributor to changes in tumor cellmetabolism to the glycolytic pathway. Id. The OCT1 transcription factor,another potential target for chemotherapeutics, may cooperate with p53in regulating tumor cell metabolism. Id.

Pyruvate kinate M2 (PKM2) promotes changes in cellular metabolism whichconfer metabolic advantages to cancer cells by supporting cellproliferation. Id. For example, lung cancer cells which express PKM2over PKM1 have been found to have such an advantage. Id. In the clinic,PKM2 has been identified as being overexpressed in a number of cancertypes. Id. Thus PKM2 may be a useful biomarker for the early detectionof tumors.

Mutations in isocitrate dehydrogenases IDH1 and IDH2 have been linked totumorigenesis, specifically, in glioblastoma and acute myeloid leukemia.See Mardis, E. R. et al., N. Engl. J. Med., 2009, 361: 1058-1066;Parsons, D. W. et al., Science, 2008, 321: 1807-1812.

The incidence of cancer continues to climb as the general populationages, as new cancers develop, and as susceptible populations (e.g.,people infected with AIDS, the elderly or excessively exposed tosunlight) grow. A tremendous demand therefore exists for new methods,treatments and compositions that can be used to treat patients withcancer including but not limited to those with lymphoma, NHL, multiplemyeloma, AML, leukemias, and solid tumors.

Accordingly, compounds that can control and/or inhibit unwantedangiogenesis or inhibit the production of certain cytokines, includingTNF-α, may be useful in the treatment and prevention of various forms ofcancer.

Methods of Treating Cancer

Current cancer therapy may involve surgery, chemotherapy, hormonaltherapy and/or radiation treatment to eradicate neoplastic cells in apatient (see, for example, Stockdale, 1998, Medicine, vol. 3, Rubensteinand Federman, eds., Chapter 12, Section IV). Recently, cancer therapycould also involve biological therapy or immunotherapy. All of theseapproaches may pose significant drawbacks for the patient. Surgery, forexample, may be contraindicated due to the health of a patient or may beunacceptable to the patient. Additionally, surgery may not completelyremove neoplastic tissue. Radiation therapy is only effective when theneoplastic tissue exhibits a higher sensitivity to radiation than normaltissue. Radiation therapy can also often elicit serious side effects.Hormonal therapy is rarely given as a single agent. Although hormonaltherapy can be effective, it is often used to prevent or delayrecurrence of cancer after other treatments have removed the majority ofcancer cells. Certain biological and other therapies are limited innumber and may produce side effects such as rashes or swellings,flu-like symptoms, including fever, chills and fatigue, digestive tractproblems or allergic reactions.

With respect to chemotherapy, there are a variety of chemotherapeuticagents available for treatment of cancer. A number of cancerchemotherapeutics act by inhibiting DNA synthesis, either directly orindirectly by inhibiting the biosynthesis of deoxyribonucleotidetriphosphate precursors, to prevent DNA replication and concomitant celldivision. Gilman et al., Goodman and Gilman's: The Pharmacological Basisof Therapeutics, Terth Ed. (McGraw Hill, N.Y.).

Despite availability of a variety of chemotherapeutic agents,chemotherapy has many drawbacks. Stockdale, Medicine, vol. 3, Rubensteinand Federman, eds., ch. 12, sect. 10, 1998. Almost all chemotherapeuticagents are toxic, and chemotherapy causes significant and oftendangerous side effects including severe nausea, bone marrow depression,and immunosuppression. Additionally, even with administration ofcombinations of chemotherapeutic agents, many tumor cells are resistantor develop resistance to the chemotherapeutic agents. In fact, thosecells resistant to the particular chemotherapeutic agents used in thetreatment protocol often prove to be resistant to other drugs, even ifthose agents act by different mechanism from those of the drugs used inthe specific treatment. This phenomenon is referred to as multidrugresistance. Because of the drug resistance, many cancers proverefractory to standard chemotherapeutic treatment protocols.

There exists a significant need for safe and effective compounds andmethods for treating, preventing and managing cancer, including forcancers that are refractory to standard treatments, such as surgery,radiation therapy, chemotherapy and hormonal therapy, while reducing oravoiding the toxicities and/or side effects associated with theconventional therapies.

4. SUMMARY

Provided herein are compounds, pharmaceutical compositions containingthe compounds and methods of use thereof in treating cancer, includingsolid tumors and blood borne tumors. In one embodiment, the compoundsfor use in the compositions and methods provided herein are of FormulaI:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein:

R¹ is H, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl;

R² and R³ are each halo; and

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl orheterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groupsin R⁵ are each independently optionally substituted with 1-3 groups Q¹,where each Q¹ is independently alkyl, haloalkyl or halo;

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl;

R⁸ is alkyl, haloalkyl, or hydroxyalkyl;

R⁹ is alkyl or aryl;

J is O or S; and

t is 1 or 2.

Provided herein are compounds, pharmaceutical compositions containingthe compounds and methods of use thereof in treating cancer, includingsolid tumors and blood borne tumors.

In one embodiment, the compounds for use in the compositions and methodsprovided herein are of Formula I or an enantiomer or a mixture ofenantiomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof, wherein:

R¹ is H, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl;

R² and R³ are each halo; and

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, cycloalkylalkyl, —R⁴OR⁵, —R⁴N(R⁶)(R⁷), —R⁴SR⁵,—R⁴OR⁴N(R⁶)(R⁷) or —R⁴OR⁴C(J)N(R⁶)(R⁷);

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and

R⁶ and R⁷ are each independently hydrogen or alkyl.

In one embodiment, the compounds for use in the compositions and methodsprovided herein are of Formula I or an enantiomer or a mixture ofenantiomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof, wherein:

R¹ is optionally substituted cycloalkyl, aryl, heteroaryl orheterocyclyl;

R² and R³ are each halo; and

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, —R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷) or —R⁴OR⁴C(J)N(R⁶)(R⁷);

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; andR⁶ and

R⁷ are each independently hydrogen or alkyl or R⁶ and R⁷ together withthe nitrogen atom on which they are substituted form a 5 or 6-memberedheterocyclyl or heteroaryl ring, optionally substituted with one or twohalo, alkyl or haloalkyl.

In one embodiment, the compound provided herein is a compound of formulaI. In one embodiment, the compound provided herein is a pharmaceuticallyacceptable salt of the compound of formula I. In one embodiment, thecompound provided herein is a solvate of the compound of formula I. Inone embodiment, the compound provided herein is a hydrate of compound offormula I. In one embodiment, the compound provided herein is aclathrate of the compound of formula I.

Also provided are pharmaceutical compositions formulated foradministration by an appropriate route and means containing effectiveconcentrations of one or more of the compounds provided herein, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, and optionally comprising at least one pharmaceutical carrier.

In one embodiment, the pharmaceutical compositions deliver amountseffective for the treatment of cancer, including solid tumors and bloodborne tumors. In one embodiment, the pharmaceutical compositions deliveramounts effective for the prevention of cancer, including solid tumorsand blood borne tumors. In one embodiment, the pharmaceuticalcompositions deliver amounts effective for the amelioration of cancer,including solid tumors and blood borne tumors.

Also provided herein are combination therapies using one or morecompounds or compositions provided herein, or an enantiomer or a mixtureof enantiomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof in combination witha therapy e.g., another pharmaceutical agent with activity againstcancer or its symptoms. Examples of therapies within the scope of themethods include, but are not limited to, surgery, chemotherapy,radiation therapy, hormonal therapy, biological therapy, immunotherapy,and combinations thereof.

The compounds or compositions provided herein, or pharmaceuticallyacceptable derivatives thereof, may be administered simultaneously with,prior to, or after administration of one or more of the above therapies.Pharmaceutical compositions containing a compound provided herein andone or more of the above agents are also provided.

In certain embodiments, provided herein are methods of treating,preventing or ameliorating cancer, including solid tumors and bloodborne tumors, or one or more symptoms or causes thereof. In certainembodiments, provided herein are methods of preventing cancer, includingsolid tumors and blood borne tumors, or one or more symptoms or causesthereof. In certain embodiments, provided herein are methods ofameliorating cancer, including solid tumors and blood borne tumors, orone or more symptoms or causes thereof. In certain embodiments, theblood borne tumor is leukemia. In certain embodiments, methods providedherein encompass methods of treating various forms of leukemias such aschronic lymphocytic leukemia, chronic myeloid leukemia, acutelymphocytic leukemia, acute myeloid leukemia and acute myeloblasticleukemia. In certain embodiments, methods provided herein encompassmethods of preventing various forms of leukemias such as chroniclymphocytic leukemia, chronic myeloid leukemia, acute lymphocyticleukemia, acute myeloid leukemia and acute myeloblastic leukemia. Incertain embodiments, methods provided herein encompass methods ofmanaging various forms of leukemias such as chronic lymphocyticleukemia, chronic myeloid leukemia, acute lymphocytic leukemia, acutemyeloid leukemia and acute myeloblastic leukemia. The methods providedherein include treatment of leukemias that are relapsed, refractory orresistant. The methods provided herein include prevention of leukemiasthat are relapsed, refractory or resistant. The methods provided hereininclude management of leukemias that are relapsed, refractory orresistant. In one embodiment, methods provided herein encompass methodsof treating acute myeloid leukemia. In one embodiment, methods providedherein encompass methods of preventing acute myeloid leukemia. In oneembodiment, methods provided herein encompass methods of managing acutemyeloid leukemia.

In practicing the methods, effective amounts of the compounds orcompositions containing therapeutically effective concentrations of thecompounds are administered to an individual exhibiting the symptoms ofthe disease or disorder to be treated. The amounts are effective toameliorate or eliminate one or more symptoms of the disease or disorder.

Further provided is a pharmaceutical pack or kit comprising one or morecontainers filled with one or more of the ingredients of thepharmaceutical compositions. Optionally associated with suchcontainer(s) can be a notice in the form prescribed by a governmentalagency regulating the manufacture, use or sale of pharmaceuticals orbiological products, which notice reflects approval by the agency ofmanufacture, use of sale for human administration. The pack or kit canbe labeled with information regarding mode of administration, sequenceof drug administration (e.g., separately, sequentially or concurrently),or the like.

These and other aspects of the subject matter described herein willbecome evident upon reference to the following detailed description.

5. DETAILED DESCRIPTION OF THE INVENTION

Provided herein are compounds of formula I. Provided herein is anenantiomer of compounds of formula I. Provided herein is a mixture ofenantiomers of compounds of formula I. Provided herein is apharmaceutically acceptable salt of a compound of formula I. Providedherein is a pharmaceutically acceptable solvate of a compound of formulaI. Provided herein is a pharmaceutically acceptable hydrate of acompound of formula I. Provided herein is a pharmaceutically acceptableco-crystal of a compound of formula I. Provided herein is apharmaceutically acceptable clathrate of a compound of formula I.Provided herein is a pharmaceutically acceptable polymorph of a compoundof formula I. Further provided are methods of treating cancer, includingsolid tumors blood borne tumors, and pharmaceutical compositions anddosage forms useful for such methods. Further provided are methods ofpreventing cancer, including solid tumors blood borne tumors, andpharmaceutical compositions and dosage forms useful for such methods.Further provided are methods of ameliorating cancer, including solidtumors blood borne tumors, and pharmaceutical compositions and dosageforms useful for such methods. The compounds, methods and compositionsare described in detail in the sections below.

A. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications are incorporated by reference in their entirety. In theevent that there are a plurality of definitions for a term herein, thosein this section prevail unless stated otherwise.

“Alkyl” refers to a straight or branched hydrocarbon chain groupconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to ten, one to eight, one to six or one tofour carbon atoms, and which is attached to the rest of the molecule bya single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl(iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and thelike.

“Alkylene” and “alkylene chain” refer to a straight or branched divalenthydrocarbon chain consisting solely of carbon and hydrogen, containingno unsaturation and having from one to eight carbon atoms, e.g.,methylene, ethylene, propylene, n-butylene and the like. The alkylenechain may be attached to the rest of the molecule through any twocarbons within the chain.

“Alkenylene” or “alkenylene chain” refers to a straight or branchedchain unsaturated divalent radical consisting solely of carbon andhydrogen atoms, having from two to eight carbon atoms, wherein theunsaturation is present only as double bonds and wherein the double bondcan exist between any two carbon atoms in the chain, e.g., ethenylene,prop-1-enylene, but-2-enylene and the like. The alkenylene chain may beattached to the rest of the molecule through any two carbons within thechain.

“Alkoxy” refers to the group having the formula —OR wherein R is alkylor haloalkyl. An “optionally substituted alkoxy” refers to the grouphaving the formula —OR wherein R is an optionally substituted alkyl asdefined herein.

“Amino” refers to a radical having the formula —NR′R″ wherein R′ and R″are each independently hydrogen, alkyl or haloalkyl. An “optionallysubstituted amino” refers to a radical having the formula —NR′R″ whereinone or both of R′ and R″ are optionally substituted alkyl as definedherein.

“Aryl” refers to a group of carbocylic ring system, includingmonocyclic, bicyclic, tricyclic, tetracyclic C₆-C₁₈ ring systems,wherein at least one of the rings is aromatic. The aryl may be fullyaromatic, examples of which are phenyl, naphthyl, anthracenyl,acenaphthylenyl, azulenyl, fluorenyl, indenyl and pyrenyl. The aryl mayalso contain an aromatic ring in combination with a non-aromatic ring,examples of which are acenaphene, indene, and fluorene.

“Cycloalkyl” refers to a stable monovalent monocyclic or bicyclichydrocarbon group consisting solely of carbon and hydrogen atoms, havingfrom three to ten carbon atoms which is saturated, e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, decalinyl, norbornane, norbornene,adamantyl, bicyclo[2.2.2]octane and the like.

“Halo, “halogen” or “halide” refers to F, Cl, Br or I.

“Haloalkyl” refers to an alkyl group, in certain embodiments, C₁₋₆alkylgroup in which one or more of the hydrogen atoms are replaced byhalogen. Such groups include, but are not limited to, chloromethyl,trifluoromethyl 1-chloro-2-fluoroethyl, 2,2-difluoroethyl,2-fluoropropyl, 2-fluoropropan-2-yl, 2,2,2-trifluoroethyl,1,1-difluoroethyl, 1,3-difluoro-2-methylpropyl, 2,2-difluorocyclopropyl,(trifluoromethyl)cyclopropyl, 4,4-difluorocyclohexyl and2,2,2-trifluoro-1,1-dimethylethyl.

“Heterocycle” or “Heterocyclyl” refers to a stable 3- to 15-memberednon-aromatic ring radical which consists of carbon atoms and from one tofive heteroatoms selected from a group consisting of nitrogen, oxygenand sulfur. In one embodiment, the heterocyclic ring system radical maybe a monocyclic, bicyclic or tricyclic ring or tetracyclic ring system,which may include fused or bridged ring systems; and the nitrogen orsulfur atoms in the heterocyclic ring system radical may be optionallyoxidized; the nitrogen atom may be optionally quaternized; and theheterocyclyl radical may be partially or fully saturated. Theheterocyclic ring system may be attached to the main structure at anyheteroatom or carbon atom which results in the creation of a stablecompound. Exemplary heterocylic radicals include, morpholinyl,piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, oxetanyl, azetidinyl,quinuclidinyl, octahydroquinolizinyl, decahydroquinolizinyl,azabicyclo[3.2.1]octanyl, azabicyclo[2.2.2]octanyl, isoindolinyl,indolinyl and others.

“Heteroaryl” refers to a heterocyclyl group as defined above which isaromatic. The heteroaryl groups include, but are not limited tomonocyclyl, bicyclyl and tricyclyl groups, and may be attached to themain structure at any heteroatom or carbon atom which results in thecreation of a stable compound. Examples of such heteroaryl groupsinclude, but are not limited to: furanyl, imidazolyl, oxazolyl,isoxazolyl, pyrimidinyl, pyridinyl, pyridazinyl, thiazolyl, thienyl,benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyridinyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl and others.

“IC₅₀” refers to an amount, concentration or dosage of a particular testcompound that achieves a 50% inhibition of a maximal response, such ascell growth or proliferation, measured via any of the in vitro or cellbased assay described herein.

Pharmaceutically acceptable salts include, but are not limited to, aminesalts, such as but not limited to N,N′-dibenzylethylenediamine,chloroprocaine, choline, ammonia, diethanolamine and otherhydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine,N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethyl-benzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc; and other metal salts, such as but not limited to sodiumhydrogen phosphate and disodium phosphate; and also including, but notlimited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates, fumarates and organic sulfonates.

As used herein and unless otherwise indicated, the term “hydrate” meansa compound provided herein or a salt thereof, that further includes astoichiometric or non-stoichiometeric amount of water bound bynon-covalent intermolecular forces.

As used herein and unless otherwise indicated, the term “solvate” meansa solvate formed from the association of one or more solvent moleculesto a compound provided herein. The term “solvate” includes hydrates(e.g., mono-hydrate, dihydrate, trihydrate, tetrahydrate and the like).

Unless stated otherwise specifically described in the specification, itis understood that the substitution can occur on any atom of the alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group.

Where the number of any given substituent is not specified (e.g.,haloalkyl), there may be one or more substituents present. For example,“haloalkyl” may include one or more of the same or different halogens.

When the groups described herein, with the exception of alkyl group, aresaid to be “substituted,” they may be substituted with any appropriatesubstituent or substituents. Illustrative examples of substituents arethose found in the exemplary compounds and embodiments disclosed herein,as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl;alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol;thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl;acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone;sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aryloxyamine, aralkoxyamine; N-oxide; hydrazine;hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate;thiocyanate; oxygen (═O); B(OH)₂, O(alkyl)aminocarbonyl; cycloalkyl,which may be monocyclic or fused or non-fused polycyclic (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl,which may be monocyclic or fused or non-fused polycyclic (e.g.,pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl);monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g.,phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl,pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy;aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy. When the alkylgroups described herein are said to be “substituted,” they may besubstituted with any substituent or substituents as those found in theexemplary compounds and embodiments disclosed herein, as well as halogen(chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl;amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine;imide; amidine; guanidine; enamine; aminocarbonyl; acylamino;phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide;ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine;alkoxyamine; aryloxyamine, aralkoxyamine; N-oxide; hydrazine; hydrazide;hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate;B(OH)₂, or O(alkyl)aminocarbonyl.

Unless specifically stated otherwise, where a compound may assumealternative tautomeric, regioisomeric and/or stereoisomeric forms, allalternative isomers are intended to be encompassed within the scope ofthe claimed subject matter. For example, where a compound is describedas having one of two tautomeric forms, it is intended that the bothtautomers be encompassed herein.

Thus, the compounds provided herein may be enantiomerically pure, or bestereoisomeric or diastereomeric mixtures.

It is to be understood that the compounds provided herein may containchiral centers. Such chiral centers may be of either the (R) or (5)configuration, or may be a mixture thereof. It is to be understood thatthe chiral centers of the compounds provided herein may undergoepimerization in vivo. As such, one of skill in the art will recognizethat administration of a compound in its (R) form is equivalent, forcompounds that undergo epimerization in vivo, to administration of thecompound in its (S) form.

Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers maybe prepared using chiral synthons or chiral reagents, or resolved usingconventional techniques, such as chromatography on a chiral stationaryphase.

In the description herein, if there is any discrepancy between achemical name and chemical structure, the structure controls.

As used herein and unless otherwise indicated, the terms “treat,”“treating” and “treatment” refer to alleviating or reducing the severityof a symptom associated with the disease or condition being treated.

The term “prevention” includes the inhibition of a symptom of theparticular disease or disorder. In some embodiments, patients withfamilial history of cancer, including solid tumors and blood bornetumors, are candidates for preventive regimens. Generally, the term“preventing” refers to administration of the drug prior to the onset ofsymptoms, particularly to patients at risk of cancer, including solidtumors and blood borne tumors.

As used herein and unless otherwise indicated, the term “managing”encompasses preventing the recurrence of the particular disease ordisorder in a patient who had suffered from it, lengthening the time apatient who had suffered from the disease or disorder remains inremission, reducing mortality rates of the patients, and/or maintaininga reduction in severity or avoidance of a symptom associated with thedisease or condition being managed.

As used herein, “subject” is an animal, typically a mammal, including ahuman, such as a human patient.

As used herein, the term “tumor,” refers to all neoplastic cell growthand proliferation, whether malignant or benign, and all pre-cancerousand cancerous cells and tissues. “Neoplastic,” as used herein, refers toany form of dysregulated or unregulated cell growth, whether malignantor benign, resulting in abnormal tissue growth. Thus, “neoplastic cells”include malignant and benign cells having dysregulated or unregulatedcell growth.

As used herein, “hematologic malignancy” refers to cancer of the body'sblood-forming and immune system—the bone marrow and lymphatic tissue.Such cancers include leukemias, lymphomas (Non-Hodgkin's Lymphoma),Hodgkin's disease (also called Hodgkin's Lymphoma) and myeloma.

The term “leukemia” refers to malignant neoplasms of the blood-formingtissues. The leukemia includes, but is not limited to, chroniclymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblasticleukemia, acute myeloid leukemia, and acute myeloblastic leukemia. Theleukemia can be relapsed, refractory or resistant to conventionaltherapy.

As used herein, “promyelocytic leukemia” or “acute promyelocyticleukemia” refers to a malignancy of the bone marrow in which there is adeficiency of mature blood cells in the myeloid line of cells and anexcess of immature cells called promyelocytes. It is usually marked byan exchange of regions of chromosomes 15 and 17.

As used herein, “acute lymphocytic leukemia (ALL)”, also known as “acutelymphoblastic leukemia” refers to a malignant disease caused by theabnormal growth and development of early nongranular white blood cells,or lymphocytes.

As used herein, “T-cell leukemia” refers to a disease in which certaincells of the lymphoid system called T lymphocytes or T cells aremalignant. T cells are white blood cells that normally can attackvirus-infected cells, foreign cells, and cancer cells and producesubstances that regulate the immune response.

The term “relapsed” refers to a situation where patients who have had aremission of leukemia after therapy have a return of leukemia cells inthe marrow and a decrease in normal blood cells.

The term “refractory or resistant” refers to a circumstance wherepatients, even after intensive treatment, have residual leukemia cellsin their marrow.

As used herein, and unless otherwise specified, the terms“therapeutically effective amount” and “effective amount” of a compoundrefer to an amount sufficient to provide a therapeutic benefit in thetreatment, prevention and/or management of a disease, to delay orminimize one or more symptoms associated with the disease or disorder tobe treated. The terms “therapeutically effective amount” and “effectiveamount” can encompass an amount that improves overall therapy, reducesor avoids symptoms or causes of disease or disorder, or enhances thetherapeutic efficacy of another therapeutic agent.

The terms “co-administration” and “in combination with” include theadministration of two therapeutic agents (for example, a compoundprovided herein and another anti-cancer agent) either simultaneously,concurrently or sequentially with no specific time limits. In oneembodiment, both agents are present in the cell or in the patient's bodyat the same time or exert their biological or therapeutic effect at thesame time. In one embodiment, the two therapeutic agents are in the samecomposition or unit dosage form. In another embodiment, the twotherapeutic agents are in separate compositions or unit dosage forms.

The term “the supportive care agent” refers to any substance thattreats, prevents or manages an adverse effect from treatment with thecompound of Formula I.

The term “biological therapy” refers to administration of biologicaltherapeutics such as cord blood, stem cells, growth factors and thelike.

The term “about,” as used herein, unless otherwise indicated, refers toa value that is no more than 10% above or below the value being modifiedby the term. For example, the term “about 10 mg/m²” means a range offrom 9 mg/m² to 11 mg/m².

“Anti-cancer agents” refers to anti-metabolites (e.g., 5-fluoro-uracil,methotrexate, fludarabine), antimicrotubule agents (e.g., vincaalkaloids such as vincristine, vinblastine; taxanes such as paclitaxel,docetaxel), alkylating agents (e.g., cyclophosphamide, melphalan,carmustine, nitrosoureas such as bischloroethylnitrosurea andhydroxyurea), platinum agents (e.g. cisplatin, carboplatin, oxaliplatin,JM-216 or satraplatin, CI-973), anthracyclines (e.g., doxorubicin,daunorubicin), antitumor antibiotics (e.g., mitomycin, idarubicin,adriamycin, daunomycin), topoisomerase inhibitors (e.g., etoposide,camptothecins), anti-angiogenesis agents (e.g. Sutent® and Bevacizumab)or any other cytotoxic agents, (estramustine phosphate, prednimustine),hormones or hormone agonists, antagonists, partial agonists or partialantagonists, kinase inhibitors, and radiation treatment.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (see, Biochem. 1972, 11:942-944).

B. Compounds

In certain embodiments, provided herein are compounds of Formula I:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein:

R¹ is H, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted heterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

J is O or S;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl.

In certain embodiments, provided herein is a compound of Formula I,wherein:

R¹ is H, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted heterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

J is O or S;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl.

In certain embodiments, provided herein is an enantiomer of a compoundof Formula I, wherein:

R¹ is H, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted heterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

J is O or S;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl.

In certain embodiments, provided herein is a mixture of enantiomers of acompound of Formula I, wherein:

R¹ is H, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted heterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

J is O or S;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl.

In certain embodiments, provided herein is a pharmaceutically acceptablesalt of a compound of Formula I, wherein:

R¹ is H, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted heterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

J is O or S;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl.

In certain embodiments, provided herein is a solvate of a compound ofFormula I, wherein:

R¹ is H, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted heterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

J is O or S;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl.

In certain embodiments, provided herein is a hydrate of a compound ofFormula I, wherein

R¹ is H, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted heterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

J is O or S;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl.

In certain embodiments, provided herein is a co-crystal of a compound ofFormula I, wherein:

R¹ is H, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted heterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

J is O or S;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl.

In certain embodiments, provided herein is polymorph of a compound ofFormula I, wherein:

R¹ is H, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted heterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

J is O or S;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl.

In certain embodiments, provided herein are compounds of Formula I or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein:

R¹ is optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted aryl, optionally substituted heteroaryl oroptionally substituted heterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,cycloalkyl, cycloalkylalkyl, —R⁴OR⁵, —R⁴SR⁵, —R⁴N(R⁶)(R⁷),R⁴OR⁴N(R⁶)(R⁷) or R⁴OR⁴C(J)N(R⁶)(R⁷);

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and

R⁶ and R⁷ are each independently hydrogen or alkyl.

In certain embodiments, provided herein are compounds of Formula I or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein:

R¹ is optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl orheterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groupsin R⁵ are each independently optionally substituted with 1-3 Q¹ groups,where each Q¹ is independently alkyl, haloalkyl or halo;

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl;

R⁸ is alkyl, haloalkyl, or hydroxyalkyl;

R⁹ is alkyl or aryl;

J is O or S; and

t is 1 or 2.

In certain embodiments, provided herein are compounds of Formula I or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein:

R¹ is optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

where the substituents on Q, when present are one to three groups Q^(a),where each Q^(a) is independently alkyl, halo, haloalkyl, alkoxyalkyl,oxo, hydroxyl or alkoxy;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl orheterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groupsin R⁵ are each independently optionally substituted with 1-3 Q¹ groups,where each Q¹ is independently alkyl, haloalkyl or halo;

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl;

R⁸ is alkyl, haloalkyl, or hydroxyalkyl;

R⁹ is alkyl or aryl;

J is O or S; and

t is 1 or 2.

In certain embodiments, provided herein are compounds of Formula I,wherein:

R¹ is optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

where the substituents on Q, when present are one to three groups Q^(a),where each Q^(a) is independently alkyl, halo, haloalkyl, alkoxyalkyl,oxo, hydroxyl or alkoxy;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl orheterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groupsin R⁵ are each independently optionally substituted with 1-3 Q¹ groups,where each Q¹ is independently alkyl, haloalkyl or halo;

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl;

R⁸ is alkyl, haloalkyl, or hydroxyalkyl;

R⁹ is alkyl or aryl;

J is O or S; and

t is 1 or 2.

In certain embodiments, provided herein is an enatiomer of a compound ofFormula I, wherein:

R¹ is optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

where the substituents on Q, when present are one to three groups Q^(a),where each Q^(a) is independently alkyl, halo, haloalkyl, alkoxyalkyl,oxo, hydroxyl or alkoxy;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl orheterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groupsin R⁵ are each independently optionally substituted with 1-3 Q¹ groups,where each Q¹ is independently alkyl, haloalkyl or halo;

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl;

R⁸ is alkyl, haloalkyl, or hydroxyalkyl;

R⁹ is alkyl or aryl;

J is O or S; and

t is 1 or 2.

In certain embodiments, provided herein is a mixture of enatiomers of acompound of Formula I, wherein:

R¹ is optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

where the substituents on Q, when present are one to three groups Q^(a),where each Q^(a) is independently alkyl, halo, haloalkyl, alkoxyalkyl,oxo, hydroxyl or alkoxy;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl orheterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groupsin R⁵ are each independently optionally substituted with 1-3 Q¹ groups,where each Q¹ is independently alkyl, haloalkyl or halo;

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl;

R⁸ is alkyl, haloalkyl, or hydroxyalkyl;

R⁹ is alkyl or aryl;

J is O or S; and

t is 1 or 2.

In certain embodiments, provided herein is a pharmaceutically acceptablesalt of a compound of Formula I, wherein:

R¹ is optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

where the substituents on Q, when present are one to three groups Q^(a),where each Q^(a) is independently alkyl, halo, haloalkyl, alkoxyalkyl,oxo, hydroxyl or alkoxy;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl orheterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groupsin R⁵ are each independently optionally substituted with 1-3 Q¹ groups,where each Q¹ is independently alkyl, haloalkyl or halo;

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl;

R⁸ is alkyl, haloalkyl, or hydroxyalkyl;

R⁹ is alkyl or aryl;

J is O or S; and

t is 1 or 2.

In certain embodiments, provided herein is a solvate of a compound ofFormula I, wherein:

R¹ is optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

where the substituents on Q, when present are one to three groups Q^(a),where each Q^(a) is independently alkyl, halo, haloalkyl, alkoxyalkyl,oxo, hydroxyl or alkoxy;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl orheterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groupsin R⁵ are each independently optionally substituted with 1-3 Q¹ groups,where each Q¹ is independently alkyl, haloalkyl or halo;

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl;

R⁸ is alkyl, haloalkyl, or hydroxyalkyl;

R⁹ is alkyl or aryl;

J is O or S; and

t is 1 or 2.

In certain embodiments, provided herein is a hydrate of a compound ofFormula I, wherein:

R¹ is optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

where the substituents on Q, when present are one to three groups Q^(a),where each Q^(a) is independently alkyl, halo, haloalkyl, alkoxyalkyl,oxo, hydroxyl or alkoxy;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl orheterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groupsin R⁵ are each independently optionally substituted with 1-3 Q¹ groups,where each Q¹ is independently alkyl, haloalkyl or halo;

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl;

R⁸ is alkyl, haloalkyl, or hydroxyalkyl;

R⁹ is alkyl or aryl;

J is O or S; and

t is 1 or 2.

In certain embodiments, provided herein is a clathrate of a compound ofFormula I, wherein:

R¹ is optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

where the substituents on Q, when present are one to three groups Q^(a),where each Q^(a) is independently alkyl, halo, haloalkyl, alkoxyalkyl,oxo, hydroxyl or alkoxy;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl orheterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groupsin R⁵ are each independently optionally substituted with 1-3 Q¹ groups,where each Q¹ is independently alkyl, haloalkyl or halo;

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl;

R⁸ is alkyl, haloalkyl, or hydroxyalkyl;

R⁹ is alkyl or aryl;

J is O or S; and

t is 1 or 2.

In certain embodiments, provided herein is a co-crystal of a compound ofFormula I, wherein:

R¹ is optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

where the substituents on Q, when present are one to three groups Q^(a),where each Q^(a) is independently alkyl, halo, haloalkyl, alkoxyalkyl,oxo, hydroxyl or alkoxy;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl orheterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groupsin R⁵ are each independently optionally substituted with 1-3 Q¹ groups,where each Q¹ is independently alkyl, haloalkyl or halo;

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl;

R⁸ is alkyl, haloalkyl, or hydroxyalkyl;

R⁹ is alkyl or aryl;

J is O or S; and

t is 1 or 2.

In certain embodiments, provided herein is a polymorph of a compound ofFormula I, wherein:

R¹ is optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl;

R² and R³ are each halo;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —R⁴OR⁵, —R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷),—R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷), —R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

where the substituents on Q, when present are one to three groups Q^(a),where each Q^(a) is independently alkyl, halo, haloalkyl, alkoxyalkyl,oxo, hydroxyl or alkoxy;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl orheterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groupsin R⁵ are each independently optionally substituted with 1-3 Q¹ groups,where each Q¹ is independently alkyl, haloalkyl or halo;

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl;

R⁸ is alkyl, haloalkyl, or hydroxyalkyl;

R⁹ is alkyl or aryl;

J is O or S; and

t is 1 or 2.

In one embodiment, provided herein are compounds of Formula II:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein:

R¹ is optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, —R⁴OR⁵, —R⁴SR⁵,—R⁴N(R⁶)(R⁷), R⁴OR⁴N(R⁶)(R⁷) or R⁴OR⁴C(J)N(R⁶)(R⁷);

J is O or S;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl.

In one embodiment, provided herein is a compound of Formula II, whereinthe substituents are as described above.

In one embodiment, provided herein is an enantiomer of a compound ofFormula II, wherein the substituents are as described above.

In one embodiment, provided herein is a mixture of enantiomers of acompound of Formula II, wherein the substituents are as described above.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula II, wherein the substituents are as describedabove.

In one embodiment, provided herein is a solvate of a compound of FormulaII, wherein the substituents are as described above.

In one embodiment, provided herein is a hydrate of a compound of FormulaII, wherein the substituents are as described above.

In one embodiment, provided herein is a clathrate of a compound ofFormula II, wherein the substituents are as described above.

In one embodiment, provided herein is a co-crystal of a compound ofFormula II, wherein the substituents are as described above.

In one embodiment, provided herein is a polymorph of a compound ofFormula II, wherein the substituents are as described above.

In one embodiment, the compounds have Formula I or Formula II, whereinR¹ is optionally substituted aryl;

where the substituents on R¹, when present, are one to three groups Q,where each Q is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, —R⁴OR⁵, —R⁴SR⁵,—R⁴N(R⁶)(R⁷), R⁴OR⁴N(R⁶)(R⁷) or R⁴OR⁴C(J)N(R⁶)(R⁷);

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl.

In one embodiment, the compounds have Formula I or Formula II, whereinR¹ is optionally substituted aryl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, or optionally substitutedheteroaryl, where the substituents on R¹, when present, are one to threegroups Q, where each Q is independently halo, alkyl, optionallysubstituted cycloalkyl, optionally substituted aryl, —R⁴OR⁵ or—R⁴N(R⁶)(R⁷); each R⁴ is independently a direct bond or alkylene; eachR⁵ is independently hydrogen, halo, alkyl, alkoxy, haloalkoxy orhaloalkyl; and

R⁶ and R⁷ are selected as follows:

-   -   i) R⁶ and R⁷ are each independently hydrogen or alkyl; or    -   ii) R⁶ and R⁷ together with the nitrogen atom on which they are        substituted form a 5 or 6-membered heterocyclyl or heteroaryl        ring, optionally substituted with one or two halo, alkyl or        haloalkyl.

In one embodiment, the compounds have Formula I or Formula II, whereinR¹ is optionally substituted phenyl, optionally substituted cyclohexyl,optionally substituted piperidinyl, or optionally substituted pyridyl,where the substituents on R¹, when present, are one to three groups Q,where each Q is independently halo, alkyl, —R⁴OR⁵ or —R⁴N(R⁶)(R⁷); eachR⁴ is independently a direct bond or alkylene; each R⁵ is independentlyhydrogen, halo, alkyl, alkoxy, haloalkoxy or haloalkyl; and R⁶ and R⁷are selected as follows:

-   -   i) R⁶ and R⁷ are each independently hydrogen or alkyl; or    -   ii) R⁶ and R⁷ together with the nitrogen atom on which they are        substituted form a 5 or 6-membered heterocyclyl ring.

In one embodiment, the compounds have Formula I or Formula II, whereinR¹ is optionally substituted phenyl, optionally substituted cyclohexyl,optionally substituted piperidinyl, or optionally substituted pyridyl,where the substituents on R¹, when present, are one to three groups Q,where each Q is independently chloro, bromo, fluoro, methyl, isopropyl,tert butyl, trifluromethyl, methoxy, ethoxy, isopropyloxy,methoxyethoxy, isopropyloxyethoxy, trifluoromethoxy, methylamino,dimethylamino or piperidinyl.

In one embodiment, the compounds have Formula I or Formula II, whereinR¹ is optionally substituted aryl, where the substituents on R¹, whenpresent, are one to three groups Q, where each Q is independently halo,alkyl, —R⁴OR⁵, —R⁴SR⁵ or R⁴OR⁴C(O)N(R⁶)(R⁷); each R⁴ is independently adirect bond or alkylene; each R⁵ is independently hydrogen, halo, alkylor haloalkyl; and R⁶ and R⁷ are each independently hydrogen or alkyl.

In one embodiment, the compounds have Formula I or Formula II, whereinR¹ is optionally substituted aryl, where the substituents on R¹, whenpresent, are one to three groups Q, where each Q is independentlyfluoro, chloro, methyl, —R⁴OR⁵, —R⁴N(R⁶)(R⁷), —R⁴SR⁵ orR⁴OR⁴C(O)N(R⁶)(R⁷); each R⁴ is independently a direct bond or methylene;each R⁵ is independently hydrogen, methyl, ethyl or trifluoromethyl; andR⁶ and R⁷ are each independently hydrogen or methyl.

In one embodiment, the compounds have Formula I or Formula II, whereinR¹ is optionally substituted phenyl, where the substituents on R¹, whenpresent, are one to three groups Q, where each Q is independentlyfluoro, chloro, methyl, tert butyl, —R⁴OR⁵, —R⁴N(R⁶)(R⁷), —R⁴SR⁵ orR⁴OR⁴C(O)N(R⁶)(R⁷); each R⁴ is independently a direct bond or methylene;each R⁵ is independently hydrogen, methyl, ethyl or trifluoromethyl; andR⁶ and R⁷ are each independently hydrogen or methyl.

In one embodiment, provided herein are compounds of Formula III:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein:

each Q¹ is independently alkyl, halo, haloalkyl, alkoxyalkyl, hydroxyl,alkoxy, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, —R⁴OR⁵, —R⁴SR⁵,—R⁴N(R⁶)(R⁷), R⁴OR⁴N(R⁶)(R⁷) or R⁴OR⁴C(J)N(R⁶)(R⁷);

J is O or S;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, halo, alkoxy, haloalkyl orhydroxyalkyl;

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl; and

n is 0-3.

In one embodiment, provided herein is a compound of Formula III, whereinthe substituents are as described above.

In one embodiment, provided herein is an enantiomer of a compound ofFormula III, wherein the substituents are as described above.

In one embodiment, provided herein is a mixture of enantiomers of acompound of Formula III, wherein the substituents are as describedabove.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula III, wherein the substituents are as describedabove.

In one embodiment, provided herein is a solvate of a compound of FormulaIII, wherein the substituents are as described above.

In one embodiment, provided herein is a hydrate of a compound of FormulaIII, wherein the substituents are as described above.

In one embodiment, provided herein is a clathrate of a compound ofFormula III, wherein the substituents are as described above.

In one embodiment, provided herein is a co-crystal of a compound ofFormula III, wherein the substituents are as described above.

In one embodiment, provided herein is a polymorph of a compound ofFormula III, wherein the substituents are as described above.

In one embodiment, provided herein are compounds of Formula III or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, wherein:

each Q¹ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, —R⁴OR⁵, —R⁴SR⁵,—R⁴N(R⁶)(R⁷);

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl;

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl; and

n is 0-3.

In one embodiment, the compounds herein are of Formula III, where eachQ¹ is independently hydrogen, Br, Cl, F, methyl, isopropyl, t-butyl,isopropyl, cyclopropyl, —CF₃, OH, —SCH₃, —SCF₃, —C(CH₃)₂F, —OCH3, —OCF₃,—OCH₂CH₃, —OCH(CH₃)₂, —OCH₂CF₃, —O(CH₂)₂OCH₃, —O(CH₂)₂OCH(CH₃)₂,—O(CH₂)₂O(CH₂)₂OCH₃, —NHCH₃, —N(CH₃)₂, —O(CH₂)₂-morpholinyl, piperidyl,morpholinyl, —CH₂-morpholinyl, —O(CH₂)₂-4,4-difluoro-1-piperidyl, orp-fluorophenyl.

In one embodiment, provided herein are compounds of Formula IV:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein:

Q² is hydrogen, alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, —R⁴OR⁵, —R⁴SR⁵, —R⁴N(R⁶)(R⁷),R⁴OR⁴N(R⁶)(R⁷) or R⁴OR⁴C(J)N(R⁶)(R⁷);

J is O or S;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and

R⁶ and R⁷ are each independently hydrogen or alkyl.

In one embodiment, provided herein is a compound of Formula IV, whereinthe substituents are as described above.

In one embodiment, provided herein is an enantiomer of a compound ofFormula IV, wherein the substituents are as described above.

In one embodiment, provided herein is a mixture of enantiomers of acompound of Formula IV, wherein the substituents are as described above.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula IV, wherein the substituents are as describedabove.

In one embodiment, provided herein is a solvate of a compound of FormulaIV, wherein the substituents are as described above.

In one embodiment, provided herein is a hydrate of a compound of FormulaIV, wherein the substituents are as described above.

In one embodiment, provided herein is a clathrate of a compound ofFormula IV, wherein the substituents are as described above.

In one embodiment, provided herein is a co-crystal of a compound ofFormula IV, wherein the substituents are as described above.

In one embodiment, provided herein is a polymorph of a compound ofFormula IV, wherein the substituents are as described above.

In one embodiment, the compounds herein are of Formula IV, where Q² ishydrogen, halo, alkyl, optionally substituted aryl, —R⁴OR⁵ or—R⁴N(R⁶)(R⁷); R⁴ is independently a direct bond or alkylene; R⁵ ishydrogen, alkyl or haloalkyl; and R⁶ and R⁷ are each independentlyhydrogen or alkyl. In some embodiments, Q² is hydrogen, Br, Cl, F,methyl, isopropyl, t-butyl, isopropyl, —OCH₃, —SCH₃, —C(CH₃)₂F,—OCH(CH₃)₂, —O(CH₂)₂OCH₃, or p-fluorophenyl.

In one embodiment, provided herein are compounds of Formula V:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein:

Q³ and Q⁴ are each independently hydrogen, alkyl, halo, haloalkyl,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, —R⁴OR⁵, —R⁴SR⁵, —R⁴N(R⁶)(R⁷),R⁴OR⁴N(R⁶)(R⁷) or R⁴OR⁴C(J)N(R⁶)(R⁷);

J is O or S;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, oralkoxyalkyl;

and

R⁶ and R⁷ are each independently hydrogen or alkyl.

In one embodiment, provided herein is a compound of Formula V, whereinthe substituents are as described above.

In one embodiment, provided herein is an enantiomer of a compound ofFormula V, wherein the substituents are as described above.

In one embodiment, provided herein is a mixture of enantiomers of acompound of Formula V, wherein the substituents are as described above.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula V, wherein the substituents are as describedabove.

In one embodiment, provided herein is a solvate of a compound of FormulaV, wherein the substituents are as described above.

In one embodiment, provided herein is a hydrate of a compound of FormulaV, wherein the substituents are as described above.

In one embodiment, provided herein is a clathrate of a compound ofFormula V, wherein the substituents are as described above.

In one embodiment, provided herein is a co-crystal of a compound ofFormula V, wherein the substituents are as described above.

In one embodiment, provided herein is a polymorph of a compound ofFormula V, wherein the substituents are as described above.

In one embodiment, the compounds herein are of Formula V, where Q⁴ andQ³ are each independently hydrogen, halo, alkyl, alkoxyalkyl, —R⁴OR⁵, or—R⁴N(R⁶)(R⁷); R⁴ is a direct bond or alkylene; and R⁵ is hydrogen, alkylor haloalkyl; and R⁶ and R⁷ are each independently hydrogen or alkyl. Insome such embodiments, Q⁴ and Q³ are each independently hydrogen, F,methyl, —CF₃, OH, —OCF₃, —OCH₂CH₃, OCH(CH₃)₂, —OCH₂CF₃, or —NHCH₃.

In one embodiment, the compounds herein are of Formula V, where Q⁴ ishydrogen, Q³ is hydrogen, halo, alkyl, alkoxyalkyl, —R⁴N(R⁶)(R⁷), or—R⁴OR⁵; R⁴ is a direct bond or alkylene; R⁵ is hydrogen, alkyl orhaloalkyl; and R⁶ and R⁷ are each independently hydrogen or alkyl.

In one embodiment, provided herein are compounds of Formula VI:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein:

Q⁴ and Q⁵ are each independently hydrogen, alkyl, halo, haloalkyl,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, —R⁴OR⁵, —R⁴SR⁵, —R⁴N(R⁶)(R⁷),R⁴OR⁴N(R⁶)(R⁷) or R⁴OR⁴C(J)N(R⁶)(R⁷);

J is O or S;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl, alkoxyalkyl orhydroxyalkyl; and

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl.

In one embodiment, provided herein is a compound of Formula VI, whereinthe substituents are as described above.

In one embodiment, provided herein is an enantiomer of a compound ofFormula VI, wherein the substituents are as described above.

In one embodiment, provided herein is a mixture of enantiomers of acompound of Formula VI, wherein the substituents are as described above.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula VI, wherein the substituents are as describedabove.

In one embodiment, provided herein is a solvate of a compound of FormulaVI, wherein the substituents are as described above.

In one embodiment, provided herein is a hydrate of a compound of FormulaVI, wherein the substituents are as described above.

In one embodiment, provided herein is a clathrate of a compound ofFormula VI, wherein the substituents are as described above.

In one embodiment, provided herein is a co-crystal of a compound ofFormula VI, wherein the substituents are as described above.

In one embodiment, provided herein is a polymorph of a compound ofFormula VI, wherein the substituents are as described above.

In one embodiment, the compounds herein are of Formula VI, where Q⁴ andQ⁵ are each independently hydrogen, halo, alkyl, alkoxyalkyl,—R⁴N(R⁶)(R⁷), or —R⁴OR⁵; R⁴ is a direct bond or alkylene; R⁵ ishydrogen, alkyl or haloalkyl; and R⁶ and R⁷ together with the nitrogenatom on which they are substituted form a 6-membered heterocyclyl. Insome such embodiments, Q⁴ and Q⁵ are each independently hydrogen, F, Cl,OH, methyl, —CF₃, —NHCH₃, —N(CH₃)₂, —OCF₃, —OCH₂CH₃, —OCH₂CF₃,—OCH(CH₃)₂, —O(CH₂)₂OCH₃, —O(CH₂)₂OCH(CH₃)₂, —O(CH₂)₂O(CH₂)₂OCH₃,O(CH₂)₂-morpholinyl, piperidyl, morpholinyl, —CH₂-morpholinyl, or—O(CH₂)₂-4,4-difluoro-1-piperidyl.

In one embodiment, provided herein are compounds of Formula VII:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein:

Q⁵ is hydrogen, alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl, —R⁴OR⁵,—R⁴SR⁵, —R⁴N(R⁶)(R⁷), R⁴OR⁴N(R⁶)(R⁷) or R⁴OR⁴C(J)N(R⁶)(R⁷);

J is O or S;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl, alkoxyalkyl orhydroxyalkyl; and

R⁶ and R⁷ are selected as follows:

i) R⁶ and R⁷ are each independently hydrogen or alkyl; or

ii) R⁶ and R⁷ together with the nitrogen atom on which they aresubstituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl.

In one embodiment, provided herein is a compound of Formula VII, whereinthe substituents are as described above.

In one embodiment, provided herein is an enantiomer of a compound ofFormula VII, wherein the substituents are as described above.

In one embodiment, provided herein is a mixture of enantiomers of acompound of Formula VII, wherein the substituents are as describedabove.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula VII, wherein the substituents are as describedabove.

In one embodiment, provided herein is a solvate of a compound of FormulaVII, wherein the substituents are as described above.

In one embodiment, provided herein is a hydrate of a compound of FormulaVII, wherein the substituents are as described above.

In one embodiment, provided herein is a clathrate of a compound ofFormula VII, wherein the substituents are as described above.

In one embodiment, provided herein is a co-crystal of a compound ofFormula VII, wherein the substituents are as described above.

In one embodiment, provided herein is a polymorph of a compound ofFormula VII, wherein the substituents are as described above.

In one embodiment, the compounds herein are of Formula VII, where Q⁵ ishydrogen, halo, alkyl, alkoxyalkyl, —R⁴N(R⁶)(R⁷) or —R⁴OR⁵; R⁴ is adirect bond or alkylene; and R⁵ is hydrogen, alkyl or haloalkyl; and R⁶and R⁷ together with the nitrogen atom on which they are substitutedform a 6-membered heterocyclyl. In some such embodiments, Q⁵ ishydrogen, F, Cl, methyl, piperidyl, morpholinyl, —CH₂-morpholinyl,—N(CH₃)₂, —O(CH₂)₂OCH₃, —O(CH₂)₂OCH(CH₃)₂, —O(CH₂)₂O(CH₂)₂OCH₃, or—O(CH₂)₂-4,4-difluoro-1-piperidyl.

In one embodiment, provided herein are compounds of Formula VIII:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein:

Q² and Q⁵ are each independently hydrogen, alkyl, halo, haloalkyl,hydroxyl, alkoxy, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted aryl, —R⁴OR⁵,—R⁴SR⁵, —R⁴N(R⁶)(R⁷), R⁴OR⁴N(R⁶)(R⁷) or R⁴OR⁴C(J)N(R⁶)(R⁷);

J is O or S;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and

R⁶ and R⁷ are each independently hydrogen or alkyl, or R⁶ and R⁷together with the nitrogen atom on which they are substituted form a6-membered heterocyclyl.

In one embodiment, provided herein is a compound of Formula VIII,wherein the substituents are as described above.

In one embodiment, provided herein is an enantiomer of a compound ofFormula VIII, wherein the substituents are as described above.

In one embodiment, provided herein is a mixture of enantiomers of acompound of Formula VIII, wherein the substituents are as describedabove.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula VIII, wherein the substituents are as describedabove.

In one embodiment, provided herein is a solvate of a compound of FormulaVIII, wherein the substituents are as described above.

In one embodiment, provided herein is a hydrate of a compound of FormulaVIII, wherein the substituents are as described above.

In one embodiment, provided herein is a clathrate of a compound ofFormula VIII, wherein the substituents are as described above.

In one embodiment, provided herein is a co-crystal of a compound ofFormula VIII, wherein the substituents are as described above.

In one embodiment, provided herein is a polymorph of a compound ofFormula VIII, wherein the substituents are as described above.

In one embodiment, the compounds herein are of Formula VIII, where Q²and Q⁵ are each independently hydrogen, halo, alkyl, alkoxyalkyl,optionally substituted aryl, or —R⁴OR⁵; R⁴ is a direct bond or alkylene;and R⁵ is hydrogen, alkyl or haloalkyl. In some such embodiments, Q² andQ⁵ are each independently hydrogen, F, Br, Cl, methyl, isopropyl,t-butyl, —C(CH₃)₂F, p-fluorophenyl, cyclopropyl, —N(CH₃)₂, —OCH₃,—OCH(CH₃)₂, O(CH₂)₂OCH₃, —O(CH₂)₂OCH(CH₃)₂, —O(CH₂)₂OCH₃,—O(CH₂)₂O(CH₂)₂OCH₃, —O(CH₂)₂-4,4-difluoro-1-piperidyl, —SCF₃,morpholinyl, piperidyl, or CH₂-morpholinyl.

In one embodiment, provided herein are compounds of Formula IX:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein:

each Q¹ is independently alkyl, halo, haloalkyl, alkoxyalkyl, hydroxyl,alkoxy, optionally substituted cycloalkyl; optionally substitutedcycloalkylalkyl, optionally substituted heterocyclyl, —R⁴OR⁵,—R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷), —R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷),—R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸;

J is O or S;

each R⁴ is independently alkylene, alkenylene or a direct bond;

each R⁵ is independently hydrogen, oxo, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl orheterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groupsin R⁵ are each independently optionally substituted with 1-3 Q¹ groupsselected from alkyl, haloalkyl or halo;

R⁶ and R⁷ are each independently hydrogen or alkyl;

R⁸ is alkyl, haloalkyl, or hydroxyalkyl;

R⁹ is alkyl or aryl;

J is O or S;

t is 1 or 2; and

n is 0-3.

In one embodiment, provided herein is a compound of Formula IX, whereinthe substituents are as described above.

In one embodiment, provided herein is an enantiomer of a compound ofFormula IX, wherein the substituents are as described above.

In one embodiment, provided herein is a mixture of enantiomers of acompound of Formula IX, wherein the substituents are as described above.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula IX, wherein the substituents are as describedabove.

In one embodiment, provided herein is a solvate of a compound of FormulaIX, wherein the substituents are as described above.

In one embodiment, provided herein is a hydrate of a compound of FormulaIX, wherein the substituents are as described above.

In one embodiment, provided herein is a clathrate of a compound ofFormula IX, wherein the substituents are as described above.

In one embodiment, provided herein is a co-crystal of a compound ofFormula IX, wherein the substituents are as described above.

In one embodiment, provided herein is a polymorph of a compound ofFormula IX, wherein the substituents are as described above.

In one embodiment, the compounds herein are of Formula IX, where each Q¹is independently hydrogen, halo, alkyl, haloalkyl, alkoxyalkyl orhaloalkoxyalkyl. In some embodiments, each Q¹ is independently fluoro,chloro, bromo, methyl, isopropyl, t-butyl, —CF₃, —O—CH₂CH₃, —O—CH(CH₃)₂,or cyclopropyl.

In one embodiment, the compound provided herein is selected from thegroup consisting of:

In one embodiment, the compound provided herein is a compound of Table1.

Also provided herein are isotopically enriched analogs of the compoundsprovided herein. Isotopic enrichment (for example, deuteration) ofpharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics(“PD”), and toxicity profiles, has been demonstrated previously withsome classes of drugs. See, for example, Lijinsky et. al., Food Cosmet.Toxicol., 20: 393 (1982); Lijinsky et. al., J. Nat. Cancer Inst., 69:1127 (1982); Mangold et. al., Mutation Res. 308: 33 (1994); Gordon et.al., Drug Metab. Dispos., 15: 589 (1987); Zello et. al., Metabolism, 43:487 (1994); Gately et. al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem.Biol. Interact. 117: 191 (1999).

Without being limited by any particular theory, iotopic enrichment of adrug can be used, for example, to (1) reduce or eliminate unwantedmetabolites, (2) increase the half-life of the parent drug, (3) decreasethe number of doses needed to achieve a desired effect, (4) decrease theamount of a dose necessary to achieve a desired effect, (5) increase theformation of active metabolites, if any are formed, and/or (6) decreasethe production of deleterious metabolites in specific tissues and/orcreate a more effective drug and/or a safer drug for combinationtherapy, whether the combination therapy is intentional or not.

Replacement of an atom for one of its isotopes often will result in achange in the reaction rate of a chemical reaction. This phenomenon isknown as the Kinetic Isotope Effect (“KIE”). For example, if a C—H bondis broken during a rate-determining step in a chemical reaction (i.e.the step with the highest transition state energy), substitution of adeuterium for that hydrogen will cause a decrease in the reaction rateand the process will slow down. This phenomenon is known as theDeuterium Kinetic Isotope Effect (“DKIE”). (See, e.g, Foster et al.,Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J.Physiol. Pharmacol., vol. 77, pp. 79-88 (1999)).

The magnitude of the DKIE can be expressed as the ratio between therates of a given reaction in which a C—H bond is broken, and the samereaction where deuterium is substituted for hydrogen. The DKIE can rangefrom about 1 (no isotope effect) to very large numbers, such as 50 ormore, meaning that the reaction can be fifty, or more, times slower whendeuterium is substituted for hydrogen. Without being limited by aparticular theory, high DKIE values may be due in part to a phenomenonknown as tunneling, which is a consequence of the uncertainty principle.Tunneling is ascribed to the small mass of a hydrogen atom, and occursbecause transition states involving a proton can sometimes form in theabsence of the required activation energy. Because deuterium has moremass than hydrogen, it statistically has a much lower probability ofundergoing this phenomenon.

Tritium (“T”) is a radioactive isotope of hydrogen, used in research,fusion reactors, neutron generators and radiopharmaceuticals. Tritium isa hydrogen atom that has 2 neutrons in the nucleus and has an atomicweight close to 3. It occurs naturally in the environment in very lowconcentrations, most commonly found as T₂O. Tritium decays slowly(half-life=12.3 years) and emits a low energy beta particle that cannotpenetrate the outer layer of human skin. Internal exposure is the mainhazard associated with this isotope, yet it must be ingested in largeamounts to pose a significant health risk. As compared with deuterium, alesser amount of tritium must be consumed before it reaches a hazardouslevel. Substitution of tritium (“T”) for hydrogen results in yet astronger bond than deuterium and gives numerically larger isotopeeffects.

Similarly, substitution of isotopes for other elements, including, butnot limited to, ¹³C or ¹⁴C for carbon, ³³S, ³⁴S, or ³⁶S for sulfur, ¹⁵Nfor nitrogen, and ¹⁷O or ¹⁸O for oxygen, will provide a similar kineticisotope effects.

The animal body expresses a variety of enzymes for the purpose ofeliminating foreign substances, such as therapeutic agents, from itscirculation system. Examples of such enzymes include the cytochrome P450enzymes (“CYPs”), esterases, proteases, reductases, dehydrogenases, andmonoamine oxidases, to react with and convert these foreign substancesto more polar intermediates or metabolites for renal excretion. Some ofthe most common metabolic reactions of pharmaceutical compounds involvethe oxidation of a carbon-hydrogen (C—H) bond to either a carbon-oxygen(C—O) or carbon-carbon (C—C) pi-bond. The resultant metabolites may bestable or unstable under physiological conditions, and can havesubstantially different pharmacokinetic, pharmacodynamic, and acute andlong-term toxicity profiles relative to the parent compounds. For manydrugs, such oxidations are rapid. As a result, these drugs often requirethe administration of multiple or high daily doses.

Isotopic enrichment at certain positions of a compound provided hereinmay produce a detectable KIE that affects the pharmacokinetic,pharmacologic, and/or toxicological profiles of a compound providedherein in comparison with a similar compound having a natural isotopiccomposition. In one embodiment, the deuterium enrichment is performed onthe site of C—H bond cleavage during metabolism.

C. Methods of Treatment and Prevention

In one embodiment, provided herein is a method of treating andpreventing cancer, which comprises administering to a patient a compoundprovided herein, e.g., the compound of Formula I, or an enantiomer or amixture of enantiomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

In another embodiment, provided herein is method of managing cancer,which comprises administering to a patient a compound provided herein,e.g., the compound of Formula I, or an enantiomer or a mixture ofenantiomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof.

Also provided herein are methods of treating patients who have beenpreviously treated for cancer but are non-responsive to standardtherapies, as well as those who have not previously been treated. Theinvention also encompasses methods of treating patients regardless ofpatient's age, although some diseases or disorders are more common incertain age groups. The invention further encompasses methods oftreating patients who have undergone surgery in an attempt to treat thedisease or condition at issue, as well as those who have not. Becausepatients with cancer have heterogeneous clinical manifestations andvarying clinical outcomes, the treatment given to a patient may vary,depending on his/her prognosis. The skilled clinician will be able toreadily determine without undue experimentation specific secondaryagents, types of surgery, and types of non-drug based standard therapythat can be effectively used to treat an individual patient with cancer.

As used herein, the term “cancer” includes, but is not limited to, solidtumors and blood borne tumors. The term “cancer” refers to disease ofskin tissues, organs, blood, and vessels, including, but not limited to,cancers of the bladder, bone, blood, brain, breast, cervix, chest,colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes,lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis,throat, and uterus. Specific cancers include, but are not limited to,advanced malignancy, amyloidosis, neuroblastoma, meningioma,hemangiopericytoma, multiple brain metastases, glioblastoma multiforme,glioblastoma, brain stem glioma, poor prognosis malignant brain tumor,malignant glioma, recurrent malignant glioma, anaplastic astrocytoma,anaplastic oligodendroglioma, neuroendocrine tumor, rectaladenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectalcarcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma,karotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin'slymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuselarge B-Cell lymphoma, low grade follicular lymphoma, malignantmelanoma, malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneousvasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressive, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unrescectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen independentprostate cancer, androgen dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, and leiomyoma

In certain embodiments, the cancer is a solid tumor. In certainembodiments, the solid tumor is metastatic. In certain embodiments, thesolid tumor is drug-resistant. In certain embodiments, the solid tumoris hepatocellular carcinoma, prostate cancer, ovarian cancer, orglioblastoma.

In certain embodiments, the cancer is a blood borne tumor. In certainembodiments, the blood borne tumor is metastatic. In certainembodiments, the blood borne tumor is drug resistant. In certainembodiments, the cancer is leukemia.

In one embodiment, methods provided herein encompass treating,preventing or managing various types of leukemias such as chroniclymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), acutelymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and acutemyeloblastic leukemia (AML) by administering a therapeutically effectiveamount of a compound of formula I or an enantiomer or a mixture ofenantiomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof.

In some embodiments, the methods provided herein encompass treating,preventing or managing acute leukemia in a subject. In some embodiments,the acute leukemia is acute myeloid leukemia (AML), which includes, butis not limited to, undifferentiated AML (M0), myeloblastic leukemia(M1), myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3variant [M3V]), myelomonocytic leukemia (M4 or M4 variant witheosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), andmegakaryoblastic leukemia (M7). In one embodiment, the acute myeloidleukemia is undifferentiated AML (M0). In one embodiment, the acutemyeloid leukemia is myeloblastic leukemia (M1). In one embodiment, theacute myeloid leukemia is myeloblastic leukemia (M2). In one embodiment,the acute myeloid leukemia is promyelocytic leukemia (M3 or M3 variant[M3V]). In one embodiment, the acute myeloid leukemia is myelomonocyticleukemia (M4 or M4 variant with eosinophilia [M4E]). In one embodiment,the acute myeloid leukemia is monocytic leukemia (M5). In oneembodiment, the acute myeloid leukemia is erythroleukemia (M6). In oneembodiment, the acute myeloid leukemia is megakaryoblastic leukemia(M7). Thus, the methods of treating, preventing or managing acutemyeloid leukemia in a subject comprise the step of administering to thesubject an amount of a compound provided herein or an enantiomer or amixture of enantiomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof effectiveto treat, prevent or manage acute myeloid leukemia alone or incombination. In some embodiments, the methods comprise the step ofadministering to the subject a compound provided herein or an enantiomeror a mixture of enantiomers thereof, or a pharmaceutically acceptablesalt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof incombination with a second active agent in amounts effective to treat,prevent or manage acute myeloid leukemia.

In some embodiments, the methods provided herein encompass treating,preventing or managing acute lymphocytic leukemia (ALL) in a subject. Insome embodiments, acute lymphocytic leukemia includes leukemia thatoriginates in the blast cells of the bone marrow (B-cells), thymus(T-cells), and lymph nodes. The acute lymphocytic leukemia can becategorized according to the French-American-British (FAB) MorphologicalClassification Scheme as L1—Mature-appearing lymphoblasts (T-cells orpre-B-cells), L2—Immature and pleomorphic (variously shaped)lymphoblasts (T-cells or pre-B-cells), and L3—Lymphoblasts (B-cells;Burkitt's cells). In one embodiment, the acute lymphocytic leukemiaoriginates in the blast cells of the bone marrow (B-cells). In oneembodiment, the acute lymphocytic leukemia originates in the thymus(T-cells). In one embodiment, the acute lymphocytic leukemia originatesin the lymph nodes. In one embodiment, the acute lymphocytic leukemia isL1 type characterized by mature-appearing lymphoblasts (T-cells orpre-B-cells). In one embodiment, the acute lymphocytic leukemia is L2type characterized by immature and pleomorphic (variously shaped)lymphoblasts (T-cells or pre-B-cells). In one embodiment, the acutelymphocytic leukemia is L3 type characterized by lymphoblasts (B-cells;Burkitt's cells). In certain embodiments, the acute lymphocytic leukemiais T-cell leukemia. In one embodiment, the T-cell leukemia is peripheralT-cell leukemia. In another embodiment, the T-cell leukemia is T-celllymphoblastic leukemia. In another embodiment, the T-cell leukemia iscutaneous T-cell leukemia. In another embodiment, the T-cell leukemia isadult T-cell leukemia. Thus, the methods of treating, preventing ormanaging acute lymphocytic leukemia in a subject comprise the step ofadministering to the subject an amount of a compound provided herein oran enantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof effective to treat, prevent or manage acute lymphocytic leukemiaalone or in combination with a second active agent. In some embodiments,the methods comprise the step of administering to the subject a compoundprovided herein or an enantiomer or a mixture of enantiomers thereof, ora pharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof in combination with a second activeagent in amounts effective to treat, prevent or manage acute lymphocyticleukemia.

In some embodiments, the methods provided herein encompass treating,preventing or managing chronic myelogenous leukemia (CML) in a subject.The methods comprise the step of administering to the subject an amountof a compound provided herein or an enantiomer or a mixture ofenantiomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof effective to treat,prevent or manage chronic myelogenous leukemia. In some embodiments, themethods comprise the step of administering to the subject a compoundprovided herein or an enantiomer or a mixture of enantiomers thereof, ora pharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof in combination with a second activeagent in amounts effective to treat, prevent or manage chronicmyelogenous leukemia.

In some embodiments, the methods provided herein encompass treating,preventing or managing chronic lymphocytic leukemia (CLL) in a subject.The methods comprise the step of administering to the subject an amountof a compound provided herein or an enantiomer or a mixture ofenantiomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof effective to treat,prevent or manage chronic lymphocytic leukemia. In some embodiments, themethods comprise the step of administering to the subject a compoundprovided herein or an enantiomer or a mixture of enantiomers thereof, ora pharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof in combination with a second activeagent in amounts effective to treat, prevent or manage chroniclymphocytic leukemia.

In certain embodiments, provided herein are methods of treating,preventing, and/or managing disease in patients with impaired renalfunction. In certain embodiments, provided herein are method oftreating, preventing, and/or managing cancer in patients with impairedrenal function. In certain embodiments, provided herein are methods ofproviding appropriate dose adjustments for patients with impaired renalfunction due to, but not limited to, disease, aging, or other patientfactors.

In certain embodiments, provided herein are methods of treating,preventing, and/or managing lymphoma, including non-Hodgkin's lymphoma.In some embodiments, provided herein are methods for the treatment ormanagement of non-Hodgkin's lymphoma (NHL), including but not limitedto, diffuse large B-cell lymphoma (DLBCL), using prognostic factors.

In certain embodiments, provided herein are methods of treating,preventing, and/or managing multiple myeloma, includingrelapsed/refractory multiple myeloma in patients with impaired renalfunction or a symptom thereof, comprising administering atherapeutically effective amount of the compound of Formula I, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, tautomer or racemicmixtures thereof to a patient having relapsed/refractory multiplemyeloma with impaired renal function.

In certain embodiments, a therapeutically or prophylactically effectiveamount of the compound is from about 0.005 to about 1,000 mg per day,from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mgper day, from about 0.01 to about 100 mg per day, from about 0.1 toabout 100 mg per day, from about 0.5 to about 100 mg per day, from about1 to about 100 mg per day, from about 0.01 to about 50 mg per day, fromabout 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day,from about 1 to about 50 mg per day, from about 0.02 to about 25 mg perday, from about 0.05 to about 10 mg per day, from about 0.05 to about 5mg per day, from about 0.1 to about 5 mg per day, or from about 0.5 toabout 5 mg per day.

In certain embodiments, the therapeutically or prophylacticallyeffective amount is about 0.1, about 0.2, about 0.5, about 1, about 2,about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10,about 15, about 20, about 25, about 30, about 40, about 45, about 50,about 60, about 70, about 80, about 90, about 100, or about 150 mg perday. In some such embodiments, the therapeutically or prophylacticallyeffective amount is about 2, about 3, about 4, about 5, about 6 or about7 mg per day.

In one embodiment, the recommended daily dose range of the compound ofFormula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, for the conditions described herein liewithin the range of from about 0.5 mg to about 50 mg per day, preferablygiven as a single once-a-day dose, or in divided doses throughout a day.In some embodiments, the dosage ranges from about 1 mg to about 50 mgper day. In other embodiments, the dosage ranges from about 0.5 to about5 mg per day. Specific doses per day include 0.1, 0.2, 0.5, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49 or 50 mg per day.

In a specific embodiment, the recommended starting dosage may be 0.5, 1,2, 3, 4, 5, 10, 15, 20, 25 or 50 mg per day. In another embodiment, therecommended starting dosage may be 0.5, 1, 2, 3, 4, or 5 mg per day. Thedose may be escalated to 15, 20, 25, 30, 35, 40, 45 and 50 mg/day. In aspecific embodiment, the compound can be administered in an amount ofabout 25 mg/day to patients with leukemia, including AML. In aparticular embodiment, the compound can be administered in an amount ofabout 10 mg/day to patients with leukemia, including AML. In aparticular embodiment, the compound can be administered in an amount ofabout 5 mg/day to patients with leukemia, including AML. In a particularembodiment, the compound can be administered in an amount of about 4mg/day to patients with leukemia, including AML. In a particularembodiment, the compound can be administered in an amount of about 3mg/day to patients with leukemia, including AML.

In certain embodiments, the therapeutically or prophylacticallyeffective amount is from about 0.001 to about 100 mg/kg/day, from about0.01 to about 50 mg/kg/day, from about 0.01 to about 25 mg/kg/day, fromabout 0.01 to about 10 mg/kg/day, from about 0.01 to about 9 mg/kg/day,0.01 to about 8 mg/kg/day, from about 0.01 to about 7 mg/kg/day, fromabout 0.01 to about 6 mg/kg/day, from about 0.01 to about 5 mg/kg/day,from about 0.01 to about 4 mg/kg/day, from about 0.01 to about 3mg/kg/day, from about 0.01 to about 2 mg/kg/day, from about 0.01 toabout 1 mg/kg/day, or from about 0.01 to about 0.05 mg/kg/day.

The administered dose can also be expressed in units other thanmg/kg/day. For example, doses for parenteral administration can beexpressed as mg/m²/day. One of ordinary skill in the art would readilyknow how to convert doses from mg/kg/day to mg/m²/day to given eitherthe height or weight of a subject or both (see,www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 1mg/kg/day for a 65 kg human is approximately equal to 38 mg/m²/day.

In certain embodiments, the amount of the compound administered issufficient to provide a plasma concentration of the compound at steadystate, ranging from about 0.001 to about 500 μM, about 0.002 to about200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM, fromabout 1 to about 50 μM, about 0.02 to about 25 μM, from about 0.05 toabout 20 μM, from about 0.1 to about 20 μM, from about 0.5 to about 20μM, or from about 1 to about 20 μM.

In other embodiments, the amount of the compound administered issufficient to provide a plasma concentration of the compound at steadystate, ranging from about 5 to about 100 nM, about 5 to about 50 nM,about 10 to about 100 nM, about 10 to about 50 nM or from about 50 toabout 100 nM.

As used herein, the term “plasma concentration at steady state” is theconcentration reached after a period of administration of a compoundprovided herein, e.g., the compound of Formula I, or an enantiomer or amixture of enantiomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof. Oncesteady state is reached, there are minor peaks and troughs on the timedependent curve of the plasma concentration of the compound.

In certain embodiments, the amount of the compound administered issufficient to provide a maximum plasma concentration (peakconcentration) of the compound, ranging from about 0.001 to about 500μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01to about 50 μM, from about 1 to about 50 μM, about 0.02 to about 25 μM,from about 0.05 to about 20 μM, from about 0.1 to about 20 μM, fromabout 0.5 to about 20 μM, or from about 1 to about 20 μM.

In certain embodiments, the amount of the compound administered issufficient to provide a minimum plasma concentration (troughconcentration) of the compound, ranging from about 0.001 to about 500μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01to about 50 μM, from about 1 to about 50 μM, about 0.01 to about 25 μM,from about 0.01 to about 20 μM, from about 0.02 to about 20 μM, fromabout 0.02 to about 20 μM, or from about 0.01 to about 20 μM.

In certain embodiments, the amount of the compound administered issufficient to provide an area under the curve (AUC) of the compound,ranging from about 100 to about 100,000 ng*hr/mL, from about 1,000 toabout 50,000 ng*hr/mL, from about 5,000 to about 25,000 ng*hr/mL, orfrom about 5,000 to about 10,000 ng*hr/mL.

In certain embodiments, the patient to be treated with one of themethods provided herein has not been treated with anticancer therapyprior to the administration of the compound of Formula I, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof. In certain embodiments, the patient to be treated with one ofthe methods provided herein has been treated with anticancer therapyprior to the administration of the compound of Formula I, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof. In certain embodiments, the patient to be treated with one ofthe methods provided herein has developed drug resistance to theanticancer therapy.

The methods provided herein encompass treating a patient regardless ofpatient's age, although some diseases or disorders are more common incertain age groups.

Depending on the disease to be treated and the subject's condition, thecompound of Formula I, or an enantiomer or a mixture of enantiomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate,co-crystal, clathrate, or polymorph thereof, may be administered byoral, parenteral (e.g., intramuscular, intraperitoneal, intravenous,CIV, intracistemal injection or infusion, subcutaneous injection, orimplant), inhalation, nasal, vaginal, rectal, sublingual, or topical(e.g., transdermal or local) routes of administration. The compound ofFormula I, or an enantiomer or a mixture of enantiomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, may be formulated, alone or together,in suitable dosage unit with pharmaceutically acceptable excipients,carriers, adjuvants and vehicles, appropriate for each route ofadministration.

In one embodiment, the compound of Formula I, or an enantiomer or amixture of enantiomers thereof; or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof, isadministered orally. In another embodiment, the compound of Formula I,or an enantiomer or a mixture of enantiomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered parenterally. In yetanother embodiment, the compound of Formula I, or an enantiomer or amixture of enantiomers thereof; or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof, isadministered intravenously.

The compound of Formula I, or an enantiomer or a mixture of enantiomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate,co-crystal, clathrate, or polymorph thereof, can be delivered as asingle dose such as, e.g., a single bolus injection, or oral tablets orpills; or over time, such as, e.g., continuous infusion over time ordivided bolus doses over time. The compound can be administeredrepeatedly if necessary, for example, until the patient experiencesstable disease or regression, or until the patient experiences diseaseprogression or unacceptable toxicity. For example, stable disease forsolid tumors generally means that the perpendicular diameter ofmeasurable lesions has not increased by 25% or more from the lastmeasurement. Response Evaluation Criteria in Solid Tumors (RECIST)Guidelines, Journal of the National Cancer Institute 92(3): 205-216(2000). Stable disease or lack thereof is determined by methods known inthe art such as evaluation of patient symptoms, physical examination,visualization of the tumor that has been imaged using X-ray, CAT, PET,or MRI scan and other commonly accepted evaluation modalities.

The compound of Formula I, or an enantiomer or a mixture of enantiomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate,co-crystal, clathrate, or polymorph thereof, can be administered oncedaily (QD), or divided into multiple daily doses such as twice daily(BID), three times daily (TID), and four times daily (QID). In addition,the administration can be continuous (i.e., daily for consecutive daysor every day), intermittent, e.g., in cycles (i.e., including days,weeks, or months of rest without drug). As used herein, the term “daily”is intended to mean that a therapeutic compound, such as the compound ofFormula I, is administered once or more than once each day, for example,for a period of time. The term “continuous” is intended to mean that atherapeutic compound, such as the compound of Formula I, is administereddaily for an uninterrupted period of at least 10 days to 52 weeks. Theterm “intermittent” or “intermittently” as used herein is intended tomean stopping and starting at either regular or irregular intervals. Forexample, intermittent administration of the compound of Formula I isadministration for one to six days per week, administration in cycles(e.g., daily administration for two to eight consecutive weeks, then arest period with no administration for up to one week), oradministration on alternate days. The term “cycling” as used herein isintended to mean that a therapeutic compound, such as the compound ofFormula I, is administered daily or continuously but with a rest period.In some such embodiments, administration is once a day for two to sixdays, then a rest period with no administration for five to seven days.

In some embodiments, the frequency of administration is in the range ofabout a daily dose to about a monthly dose. In certain embodiments,administration is once a day, twice a day, three times a day, four timesa day, once every other day, twice a week, once every week, once everytwo weeks, once every three weeks, or once every four weeks. In oneembodiment, the compound of Formula I, or an enantiomer or a mixture ofenantiomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof, is administeredonce a day. In another embodiment, the compound of Formula I, or anenantiomer or a mixture of enantiomers thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, is administered twice a day. In yet another embodiment, thecompound of Formula I, or an enantiomer or a mixture of enantiomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate,co-crystal, clathrate, or polymorph thereof, is administered three timesa day. In still another embodiment, the compound of Formula I, or anenantiomer or a mixture of enantiomers thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, is administered four times a day.

In certain embodiments, the compound of Formula I, or an enantiomer or amixture of enantiomers thereof; or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof, isadministered once per day from one day to six months, from one week tothree months, from one week to four weeks, from one week to three weeks,or from one week to two weeks. In certain embodiments, the compound ofFormula I, or a pharmaceutically acceptable salt or solvate thereof, isadministered once per day for one week, two weeks, three weeks, or fourweeks. In one embodiment, the compound of Formula I, or an enantiomer ora mixture of enantiomers thereof; or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof, isadministered once per day for 4 days. In one embodiment, the compound ofFormula I, or an enantiomer or a mixture of enantiomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered once per day for 5days. In one embodiment, the compound of Formula I, or an enantiomer ora mixture of enantiomers thereof; or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof, isadministered once per day for 6 days. In one embodiment, the compound ofFormula I, or an enantiomer or a mixture of enantiomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered once per day for oneweek. In another embodiment, the compound of Formula I, or an enantiomeror a mixture of enantiomers thereof; or a pharmaceutically acceptablesalt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, isadministered once per day for two weeks. In yet another embodiment, thecompound of Formula I, or an enantiomer or a mixture of enantiomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate,co-crystal, clathrate, or polymorph thereof, is administered once perday for three weeks. In still another embodiment, the compound ofFormula I, or an enantiomer or a mixture of enantiomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered once per day for fourweeks.

C-1. Combination Therapy with a Second Active Agent

The compound of Formula I, or an enantiomer or a mixture of enantiomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate,co-crystal, clathrate, or polymorph thereof, can also be combined orused in combination with other therapeutic agents useful in thetreatment and/or prevention of cancer described herein.

In one embodiment, provided herein is a method of treating, preventing,or managing cancer, comprising administering to a patient a compound ofFormula I, or an enantiomer or a mixture of enantiomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof; in combination with one or more secondactive agents, and optionally in combination with radiation therapy,blood transfusions, or surgery. Examples of second active agents aredisclosed herein (see, e.g., section 5.4).

As used herein, the term “in combination” includes the use of more thanone therapy (e.g., one or more prophylactic and/or therapeutic agents).However, the use of the term “in combination” does not restrict theorder in which therapies (e.g., prophylactic and/or therapeutic agents)are administered to a patient with a disease or disorder. A firsttherapy (e.g., a prophylactic or therapeutic agent such as a compoundprovided herein, a compound provided herein, e.g., the compound ofFormula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof) can be administered prior to (e.g., 5minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before),concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks,5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of asecond therapy (e.g., a prophylactic or therapeutic agent) to thesubject. Triple therapy is also contemplated herein.

Administration of the compound of Formula I and one or more secondactive agents to a patient can occur simultaneously or sequentially bythe same or different routes of administration. The suitability of aparticular route of administration employed for a particular activeagent will depend on the active agent itself (e.g., whether it can beadministered orally without decomposing prior to entering the bloodstream) and the cancer being treated.

The route of administration of the compound of Formula I is independentof the route of administration of a second therapy. In one embodiment,the compound of Formula I is administered orally. In another embodiment,the compound of Formula I is administered intravenously. Thus, inaccordance with these embodiments, the compound of Formula I isadministered orally or intravenously, and the second therapy can beadministered orally, parenterally, intraperitoneally, intravenously,intraarterially, transdermally, sublingually, intramuscularly, rectally,transbuccally, intranasally, liposomally, via inhalation, vaginally,intraoccularly, via local delivery by catheter or stent, subcutaneously,intraadiposally, intraarticularly, intrathecally, or in a slow releasedosage form. In one embodiment, the compound of Formula I and a secondtherapy are administered by the same mode of administration, orally orby IV. In another embodiment, the compound of Formula I is administeredby one mode of administration, e.g., by IV, whereas the second agent (ananticancer agent) is administered by another mode of administration,e.g., orally.

In one embodiment, the second active agent is administered intravenouslyor subcutaneously and once or twice daily in an amount of from about 1to about 1000 mg, from about 5 to about 500 mg, from about 10 to about350 mg, or from about 50 to about 200 mg. The specific amount of thesecond active agent will depend on the specific agent used, the type ofdisease being treated or managed, the severity and stage of disease, andthe amount of the compound of Formula I provided herein and any optionaladditional active agents concurrently administered to the patient.

One or more second active ingredients or agents can be used togetherwith the compound of formula I in the methods and compositions providedherein. Second active agents can be large molecules (e.g., proteins) orsmall molecules (e.g., synthetic inorganic, organometallic, or organicmolecules).

Examples of large molecule active agents include, but are not limitedto, hematopoietic growth factors, cytokines, and monoclonal andpolyclonal antibodies, particularly, therapeutic antibodies to cancerantigens. Typical large molecule active agents are biological molecules,such as naturally occurring or synthetic or recombinant proteins.Proteins that are particularly useful in the methods and compositionsprovided herein include proteins that stimulate the survival and/orproliferation of hematopoietic precursor cells and immunologicallyactive poietic cells in vitro or in vivo. Other useful proteinsstimulate the division and differentiation of committed erythroidprogenitors in cells in vitro or in vivo. Particular proteins include,but are not limited to: interleukins, such as IL-2 (includingrecombinant IL-II (“rIL2”) and canarypox IL-2), IL-10, IL-12, and IL-18;interferons, such as interferon alfa-2a, interferon alfa-2b, interferonalfa-n1, interferon alfa-n3, interferon beta-I a, and interferon gamma-Ib; GM-CF and GM-CSF; and EPO.

In certain embodiments, GM-CSF, G-CSF, SCF or EPO is administeredsubcutaneously during about five days in a four or six week cycle in anamount ranging from about 1 to about 750 mg/m²/day, from about 25 toabout 500 mg/m²/day, from about 50 to about 250 mg/m²/day, or from about50 to about 200 mg/m²/day. In certain embodiments, GM-CSF may beadministered in an amount of from about 60 to about 500 mcg/m²intravenously over 2 hours or from about 5 to about 12 mcg/m²/daysubcutaneously. In certain embodiments, G-CSF may be administeredsubcutaneously in an amount of about 1 mcg/kg/day initially and can beadjusted depending on rise of total granulocyte counts. The maintenancedose of G-CSF may be administered in an amount of about 300 (in smallerpatients) or 480 mcg subcutaneously. In certain embodiments, EPO may beadministered subcutaneously in an amount of 10,000 Unit 3 times perweek.

Particular proteins that can be used in the methods and compositionsinclude, but are not limited to: filgrastim, which is sold in the UnitedStates under the trade name Neupogen® (Amgen, Thousand Oaks, Calif.);sargramostim, which is sold in the United States under the trade nameLeukine® (Immunex, Seattle, Wash.); and recombinant EPO, which is soldin the United States under the trade name Epogen® (Amgen, Thousand Oaks,Calif.).

Recombinant and mutated forms of GM-CSF can be prepared as described inU.S. Pat. Nos. 5,391,485; 5,393,870; and 5,229,496; all of which areincorporated herein by reference. Recombinant and mutated forms of G-CSFcan be prepared as described in U.S. Pat. Nos. 4,810,643; 4,999,291;5,528,823; and 5,580,755; the entireties of which are incorporatedherein by reference.

Also provided for use in combination with a compound provided herein oran enantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof are native, naturally occurring, and recombinant proteins.Further encompassed are mutants and derivatives (e.g., modified forms)of naturally occurring proteins that exhibit, in vivo, at least some ofthe pharmacological activity of the proteins upon which they are based.Examples of mutants include, but are not limited to, proteins that haveone or more amino acid residues that differ from the correspondingresidues in the naturally occurring forms of the proteins. Alsoencompassed by the term “mutants” are proteins that lack carbohydratemoieties normally present in their naturally occurring forms (e.g.,nonglycosylated forms). Examples of derivatives include, but are notlimited to, pegylated derivatives and fusion proteins, such as proteinsformed by fusing IgG1 or IgG3 to the protein or active portion of theprotein of interest. See, e.g., Penichet, M. L. and Morrison, S. L., J.Immunol. Methods 248:91-101 (2001).

Antibodies that can be used in combination with a compound providedherein or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof include monoclonal and polyclonalantibodies. Examples of antibodies include, but are not limited to,trastuzumab (Herceptin®), rituximab (Rituxan®), bevacizumab (Avastin™)pertuzumab (Omnitarg™), tositumomab (Bexxar®), edrecolomab (Panorex®),and G250. The compounds provided herein or an enantiomer or a mixture ofenantiomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof can also becombined with, or used in combination with, anti-TNF-α antibodies,and/or anti-EGFR antibodies, such as, for example, Erbitux® orpanitumumab.

Large molecule active agents may be administered in the form ofanti-cancer vaccines. For example, vaccines that secrete, or cause thesecretion of, cytokines such as IL-2, G-CSF, and GM-CSF can be used inthe methods and pharmaceutical compositions provided. See, e.g., Emens,L. A., et al., Curr. Opinion Mol. Ther. 3(1):77-84 (2001).

Second active agents that are small molecules can also be used toalleviate adverse effects associated with the administration of acompound provided herein or an enantiomer or a mixture of enantiomersthereof, or a pharmaceutically acceptable salt, solvate, hydrate,co-crystal, clathrate, or polymorph thereof. However, like some largemolecules, many are believed to be capable of providing a synergisticeffect when administered with (e.g., before, after or simultaneously) acompound provided herein or an enantiomer or a mixture of enantiomersthereof, or a pharmaceutically acceptable salt, solvate, hydrate,co-crystal, clathrate, or polymorph thereof. Examples of small moleculesecond active agents include, but are not limited to, anti-canceragents, antibiotics, immunosuppressive agents, and steroids.

In certain embodiments, the second agent is an HSP inhibitor, aproteasome inhibitor, a FLT3 inhibitor or a TOR kinase inhibitor.

Examples of anti-cancer agents to be used within the methods orcompositions described herein include, but are not limited to: acivicin;aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin;altretamine; ambomycin; ametantrone acetate; amsacrine; anastrozole;anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin;batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafidedimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine;busulfan; cactinomycin; calusterone; caracemide; carbetimer;carboplatin; carmustine; carubicin hydrochloride; carzelesin;cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; cirolemycin;cisplatin; cladribine; clofarabine; crisnatol mesylate;cyclophosphamide; Ara-C; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; omacetaxine; ormaplatin; oxisuran;paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine;simtrazene; sorafenib; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other anti-cancer drugs to be included within the methods orcompositions include, but are not limited to: 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; Ara-C ocfosfate; cytolytic factor; cytostatin;dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone;dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox;diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin;diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine;doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib(e.g., Gleevec®); imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetiumtexaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A;marimastat; masoprocol; maspin; matrilysin inhibitors; matrixmetalloproteinase inhibitors; menogaril; merbarone; meterelin;methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine;mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide;mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene;molgramostim; Erbitux, human chorionic gonadotrophin; monophosphoryllipid A+myobacterium cell wall sk; mopidamol; mustard anticancer agent;mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxidemodulators; nitroxide antioxidant; nitrullyn; oblimersen (Genasense®);O⁶-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RH retinamide; rohitukine;romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin;SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine;senescence derived inhibitor 1; sense oligonucleotides; signaltransduction inhibitors; sizofiran; sobuzoxane; sodium borocaptate;sodium phenylacetate; solverol; somatomedin binding protein; sonermin;sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin1; squalamine; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; tallimustine; tamoxifen methiodide; tauromustine;tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomeraseinhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; translation inhibitors; tretinoin;triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron;turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors;ubenimex; urogenital sinus-derived growth inhibitory factor; urokinasereceptor antagonists; vapreotide; variolin B; velaresol; veramine;verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

Specific second active agents particularly useful in the methods orcompositions include, but are not limited to, rituximab, oblimersen(Genasense®), remicade, docetaxel, celecoxib, melphalan,dexamethasone)(Decadron®), steroids, gemcitabine, cisplatinum,temozolomide, etoposide, cyclophosphamide, temodar, carboplatin,procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa®,taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11,interferon alpha, pegylated interferon alpha (e.g., PEG INTRON-A),capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomaldaunorubicin, Ara-C, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF,dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine,doxorubicin)(Doxil®, paclitaxel, ganciclovir, adriamycin, estramustinesodium phosphate)(Emcyt®, sulindac, and etoposide.

In certain embodiments of the methods provided herein, use of a secondactive agent in combination with a compound provided herein or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof may be modified or delayed during or shortly followingadministration of a compound provided herein or an enantiomer or amixture of enantiomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof as deemedappropriate by the practitioner of skill in the art. In certainembodiments, subjects being administered a compound provided herein oran enantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof alone or in combination with other therapies may receivesupportive care including antiemetics, myeloid growth factors, andtransfusions of platelets, when appropriate. In some embodiments,subjects being administered a compound provided herein or an enantiomeror a mixture of enantiomers thereof, or a pharmaceutically acceptablesalt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof maybe administered a growth factor as a second active agent according tothe judgment of the practitioner of skill in the art. In someembodiments, provided is administration of a compound provided herein oran enantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof in combination with erythropoietin or darbepoetin (Aranesp).

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered with gemcitabine andcisplatinum to patients with locally advanced or metastatic transitionalcell bladder cancer.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered in combination with asecond active ingredient as follows: temozolomide to pediatric patientswith relapsed or progressive brain tumors or recurrent neuroblastoma;celecoxib, etoposide and cyclophosphamide for relapsed or progressiveCNS cancer; temodar to patients with recurrent or progressivemeningioma, malignant meningioma, hemangiopericytoma, multiple brainmetastases, relapased brain tumors, or newly diagnosed glioblastomamultiforms; irinotecan to patients with recurrent glioblastoma;carboplatin to pediatric patients with brain stem glioma; procarbazineto pediatric patients with progressive malignant gliomas;cyclophosphamide to patients with poor prognosis malignant brain tumors,newly diagnosed or recurrent glioblastoma multiforms; Gliadel® for highgrade recurrent malignant gliomas; temozolomide and tamoxifen foranaplastic astrocytoma; or topotecan for gliomas, glioblastoma,anaplastic astrocytoma or anaplastic oligodendroglioma.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered with methotrexate,cyclophosphamide, taxane, abraxane, lapatinib, herceptin, aromataseinhibitors, selective estrogen modulators, estrogen receptorantagonists, and/or PLX3397 (Plexxikon) to patients with metastaticbreast cancer.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered with temozolomide topatients with neuroendocrine tumors.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered with gemcitabine topatients with recurrent or metastatic head or neck cancer.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered with gemcitabine topatients with pancreatic cancer.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered to patients with coloncancer in combination with ARISA®, avastatin, taxol, and/or taxotere.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered with capecitabineand/or PLX4032 (Plexxikon) to patients with refractory colorectal canceror patients who fail first line therapy or have poor performance incolon or rectal adenocarcinoma.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered in combination withfluorouracil, leucovorin, and irinotecan to patients with Dukes C & Dcolorectal cancer or to patients who have been previously treated formetastatic colorectal cancer.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered to patients withrefractory colorectal cancer in combination with capecitabine, xeloda,and/or CPT-11.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered with capecitabine andirinotecan to patients with refractory colorectal cancer or to patientswith unresectable or metastatic colorectal carcinoma.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered alone or in combinationwith interferon alpha or capecitabine to patients with unresectable ormetastatic hepatocellular carcinoma; or with cisplatin and thiotepa topatients with primary or metastatic liver cancer.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered in combination withpegylated interferon alpha to patients with Kaposi's sarcoma.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered in combination withfludarabine, carboplatin, and/or topotecan to patients with refractoryor relapsed or high-risk acute myeloid leukemia.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered in combination withliposomal daunorubicin, topotecan and/or cytarabine to patients withunfavorable karotype acute myeloblastic leukemia.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered in combination withgemcitabine, abraxane, erlotinib, geftinib, and/or irinotecan topatients with non-small cell lung cancer.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered in combination withcarboplatin and irinotecan to patients with non-small cell lung cancer.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered with doxetaxol topatients with non-small cell lung cancer who have been previouslytreated with carbo/VP 16 and radiotherapy.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered in combination withcarboplatin and/or taxotere, or in combination with carboplatin,pacilitaxel and/or thoracic radiotherapy to patients with non-small celllung cancer.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered in combination withtaxotere to patients with stage IIIB or IV non-small cell lung cancer.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered in combination withoblimersen (Genasense®) to patients with small cell lung cancer.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered in combination withABT-737 (Abbott Laboratories) and/or obatoclax (GX15-070) to patientswith lymphoma and other blood cancers.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered alone or in combinationwith a second active ingredient such as vinblastine or fludarabine topatients with various types of lymphoma, including, but not limited to,Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma,cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma or relapsed orrefractory low grade follicular lymphoma.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered in combination withtaxotere, IL-2, IFN, GM-CSF, PLX4032 (Plexxikon) and/or dacarbazine topatients with various types or stages of melanoma.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered alone or in combinationwith vinorelbine to patients with malignant mesothelioma, or stage IIIBnon-small cell lung cancer with pleural implants or malignant pleuraleffusion mesothelioma syndrome.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered to patients withvarious types or stages of multiple myeloma in combination withdexamethasone, zoledronic acid, palmitronate, GM-CSF, biaxin,vinblastine, melphalan, busulphan, cyclophosphamide, IFN, palmidronate,prednisone, bisphosphonate, celecoxib, arsenic trioxide, PEG INTRON-A,vincristine, or a combination thereof.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered to patients withrelapsed or refractory multiple myeloma in combination with doxorubicin(Doxil®), vincristine and/or dexamethasone (Decadron®).

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered to patients withvarious types or stages of ovarian cancer such as peritoneal carcinoma,papillary serous carcinoma, refractory ovarian cancer or recurrentovarian cancer, in combination with taxol, carboplatin, doxorubicin,gemcitabine, cisplatin, xeloda, paclitaxel, dexamethasone, or acombination thereof.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered to patients withvarious types or stages of prostate cancer, in combination with xeloda,5 FU/LV, gemcitabine, irinotecan plus gemcitabine, cyclophosphamide,vincristine, dexamethasone, GM-CSF, celecoxib, taxotere, ganciclovir,paclitaxel, adriamycin, docetaxel, estramustine, Emcyt, denderon or acombination thereof.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered to patients withvarious types or stages of renal cell cancer, in combination withcapecitabine, IFN, tamoxifen, IL-2, GM-CSF, Celebrex®, or a combinationthereof.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered to patients withvarious types or stages of gynecologic, uterus or soft tissue sarcomacancer in combination with IFN, a COX-2 inhibitor such as Celebrex®,and/or sulindac.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered to patients withvarious types or stages of solid tumors in combination with celebrex,etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen,IL-2, GM-CSF, or a combination thereof.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered to patients withscleroderma or cutaneous vasculitis in combination with celebrex,etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen,IL-2, GM-CSF, or a combination thereof.

Also encompassed herein is a method of increasing the dosage of ananti-cancer drug or agent that can be safely and effectivelyadministered to a patient, which comprises administering to the patient(e.g., a human) or an enantiomer or a mixture of enantiomers thereof, ora pharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof. Patients that can benefit by thismethod are those likely to suffer from an adverse effect associated withanti-cancer drugs for treating a specific cancer of the skin,subcutaneous tissue, lymph nodes, brain, lung, liver, bone, intestine,colon, heart, pancreas, adrenal, kidney, prostate, breast, colorectal,or combinations thereof. The administration of a compound providedherein, e.g., the compound of Formula I, or an enantiomer or a mixtureof enantiomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof, alleviates orreduces adverse effects which are of such severity that it wouldotherwise limit the amount of anti-cancer drug.

In one embodiment, a compound provided herein, e.g., the compound ofFormula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered orally and daily in anamount ranging from about 0.1 to about 150 mg, from about 1 to about 50mg, or from about 2 to about 25 mg, prior to, during, or after theoccurrence of the adverse effect associated with the administration ofan anti-cancer drug to a patient. In certain embodiments, a compoundprovided herein, e.g., the compound of Formula I, or an enantiomer or amixture of enantiomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof, isadministered in combination with specific agents such as heparin,aspirin, coumadin, or G-CSF to avoid adverse effects that are associatedwith anti-cancer drugs such as but not limited to neutropenia orthrombocytopenia.

In one embodiment, a compound provided herein, e.g., the compound ofFormula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, is administered to patients withdiseases and disorders associated with or characterized by, undesiredangiogenesis in combination with additional active ingredients,including, but not limited to, anti-cancer drugs, anti-inflammatories,antihistamines, antibiotics, and steroids.

In another embodiment, encompassed herein is a method of treating,preventing and/or managing cancer, which comprises administering thecompound of Formula I, or an enantiomer or a mixture of enantiomersthereof, or a pharmaceutically acceptable salt, solvate, hydrate,co-crystal, clathrate, or polymorph thereof, in conjunction with (e.g.before, during, or after) conventional therapy including, but notlimited to, surgery, immunotherapy, biological therapy, radiationtherapy, or other non-drug based therapy presently used to treat,prevent or manage cancer. The combined use of the compound providedherein and conventional therapy may provide a unique treatment regimenthat is unexpectedly effective in certain patients. Without beinglimited by theory, it is believed that the compound of Formula I mayprovide additive or synergistic effects when given concurrently withconventional therapy.

As discussed elsewhere herein, encompassed herein is a method ofreducing, treating and/or preventing adverse or undesired effectsassociated with conventional therapy including, but not limited to,surgery, chemotherapy, radiation therapy, hormonal therapy, biologicaltherapy and immunotherapy. A compound provided herein, e.g., thecompound of Formula I, or an enantiomer or a mixture of enantiomersthereof, or a pharmaceutically acceptable salt, solvate, hydrate,co-crystal, clathrate, or polymorph thereof, and other active ingredientcan be administered to a patient prior to, during, or after theoccurrence of the adverse effect associated with conventional therapy.

In one embodiment, the compound of Formula I can be administered in anamount ranging from about 0.1 to about 150 mg, from about 1 to about 25mg, or from about 2 to about 10 mg orally and daily alone, or incombination with a second active agent disclosed herein (see, e.g.,section 5.4), prior to, during, or after the use of conventionaltherapy.

In certain embodiments, a compound provided herein, e.g., the compoundof Formula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, and doxetaxol are administered topatients with non-small cell lung cancer who were previously treatedwith carbo/VP 16 and radiotherapy.

C-2. Use with Transplantation Therapy

The compound of Formula I, or an enantiomer or a mixture of enantiomersthereof, or a pharmaceutically acceptable salt, solvate, hydrate,co-crystal, clathrate, or polymorph thereof, provided herein can be usedto reduce the risk of Graft Versus Host Disease (GVHD). Therefore,encompassed herein is a method of treating, preventing and/or managingcancer, which comprises administering the compound of Formula I, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, in conjunction with transplantation therapy.

As those of ordinary skill in the art are aware, the treatment of canceris often based on the stages and mechanism of the disease. For example,as inevitable leukemic transformation develops in certain stages ofcancer, transplantation of peripheral blood stem cells, hematopoieticstem cell preparation or bone marrow may be necessary. The combined useof the compound of Formula I, or an enantiomer or a mixture ofenantiomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof, provided hereinand transplantation therapy provides a unique and unexpected synergism.In particular, the compound of Formula I, or an enantiomer or a mixtureof enantiomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof, exhibitsimmunomodulatory activity that may provide additive or synergisticeffects when given concurrently with transplantation therapy in patientswith cancer.

The compound of Formula I, or an enantiomer or a mixture of enantiomersthereof, or a pharmaceutically acceptable salt, solvate, hydrate,co-crystal, clathrate, or polymorph thereof, can work in combinationwith transplantation therapy reducing complications associated with theinvasive procedure of transplantation and risk of GVHD. Encompassedherein is a method of treating, preventing and/or managing cancer whichcomprises administering to a patient (e.g., a human) the compound ofFormula I, or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, before, during, or after thetransplantation of umbilical cord blood, placental blood, peripheralblood stem cell, hematopoietic stem cell preparation, or bone marrow.Some examples of stem cells suitable for use in the methods providedherein are disclosed in U.S. Pat. No. 7,498,171, the disclosure of whichis incorporated herein by reference in its entirety.

In one embodiment, the compound of Formula I, or an enantiomer or amixture of enantiomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof, isadministered to patients with multiple myeloma before, during, or afterthe transplantation of autologous peripheral blood progenitor cell.

In one embodiment, the compound of Formula I, or an enantiomer or amixture of enantiomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof, isadministered to patients with NHL (e.g., DLBCL) before, during, or afterthe transplantation of autologous peripheral blood progenitor cell.

C-3. Cycling Therapy

In certain embodiments, the prophylactic or therapeutic agents providedherein are cyclically administered to a patient. Cycling therapyinvolves the administration of an active agent for a period of time,followed by a rest for a period of time, and repeating this sequentialadministration. Cycling therapy can reduce the development of resistanceto one or more of the therapies, avoid, or reduce the side effects ofone of the therapies, and/or improves the efficacy of the treatment.

Consequently, in certain embodiments, the compound of Formula I, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, provided herein is administered daily in a single or divideddoses in a four to six week cycle with a rest period of about a week ortwo weeks. The cycling method further allows the frequency, number, andlength of dosing cycles to be increased. Thus, encompassed herein incertain embodiments is the administration of a compound provided herein,e.g., the compound of Formula I, or an enantiomer or a mixture ofenantiomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof, for more cyclesthan are typical when it is administered alone. In certain embodiments,a compound provided herein, e.g., the compound of Formula I, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, is administered for a greater number of cycles that wouldtypically cause dose-limiting toxicity in a patient to whom a secondactive ingredient is not also being administered.

In one embodiment, the compound of Formula I, or an enantiomer or amixture of enantiomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof, isadministered daily and continuously for three or four weeks at a dose offrom about 0.1 to about 150 mg/d followed by a break of one or twoweeks.

In another embodiment, the compound of Formula I, or an enantiomer or amixture of enantiomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof, and asecond active ingredient are administered orally, with administration ofthe compound of Formula I occurring 30 to 60 minutes prior to a secondactive ingredient, during a cycle of four to six weeks. In certainembodiments, the combination of the compound of Formula I, or anenantiomer or a mixture of enantiomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof, and a second active ingredient is administered by intravenousinfusion over about 90 minutes every cycle. In certain embodiments, onecycle comprises the administration from about 0.1 to about 150 mg/day ofthe compound of Formula I, or an enantiomer or a mixture of enantiomersthereof, or a pharmaceutically acceptable salt, solvate, hydrate,co-crystal, clathrate, or polymorph thereof, and from about 50 to about200 mg/m²/day of a second active ingredient daily for three to fourweeks and then one or two weeks of rest. In certain embodiments, thenumber of cycles during which the combinatorial treatment isadministered to a patient is ranging from about one to about 24 cycles,from about two to about 16 cycles, or from about four to about threecycles.

D. Patient Population

In certain embodiments of the methods provided herein, the subject is ananimal, preferably a mammal, more preferably a non-human primate. Inparticular embodiments, the subject is a human. The subject can be amale or female subject.

Particularly useful subjects for the methods provided herein includehuman cancer patients, for example, those who have been diagnosed withleukemia, including acute myeloid leukemia, acute lymphocytic leukemia,chronic myelogenous leukemia, and chronic myelogenous leukemia. Incertain embodiments, the subject has not been diagnosed with acutepromyelocytic leukemia.

In some embodiments, the subject has a higher than normal blastpopulation. In some embodiments, the subject has a blast population ofat least 10%. In some embodiments, the subject has a blast population ofbetween 10 and 15%. In some embodiments, the subject has a blastpopulation of at least 15%. In some embodiments, the subject has a blastpopulation of between 15 and 20%. In some embodiments, the subject has ablast population of at least 20%. In some embodiments, the subject has ablast population of about 10-15%, about 15-20%, or about 20-25%. Inother embodiments, the subject has a blast population of less than 10%.In the context of the methods described herein, useful subjects having ablast population of less than 10% includes those subjects that, for anyreason according to the judgment of the skilled practitioner in the art,are in need of treatment with a compound provided herein, alone or incombination with a second active agent.

In some embodiments, the subject is treated based on the EasternCooperative Oncology Group (ECOG) performance status score of thesubject for leukemia. ECOG performance status can be scored on a scaleof 0 to 5, with 0 denoting asymptomatic; 1 denoting symptomatic butcompletely ambulant; 2 denoting symptomatic and <50% in bed during theday; 3 denoting symptomatic and >50% in bed, but not bed bound; 4denoting bed bound; and 5 denoting death. In some embodiments, thesubject has an ECOG performance status score of 0 or 1. In someembodiments, the subject has an ECOG performance status score of 0. Insome embodiments, the subject has an ECOG performance status score of 1.In other embodiments, the subject has an ECOG performance status scoreof 2.

In certain embodiments, the methods provided herein encompass thetreatment of subjects who have not been previously treated for leukemia.In some embodiments, the subject has not undergone allogeneic bonemarrow transplantation. In some embodiments, the subject has notundergone a stem cell transplantation. In some embodiments, the subjecthas not received hydroxyurea treatment. In some embodiments, the subjecthas not been treated with any investigational products for leukemia. Insome embodiments, the subject has not been treated with systemicglucocorticoids.

In other embodiments, the methods encompass treating subjects who havebeen previously treated or are currently being treated for leukemia. Forexample, the subject may have been previously treated or are currentlybeing treated with a standard treatment regimen for leukemia. Thesubject may have been treated with any standard leukemia treatmentregimen known to the practitioner of skill in the art. In certainembodiments, the subject has been previously treated with at least oneinduction/reinduction or consolidation AML regimen. In some embodiments,the subject has undergone autologous bone marrow transplantation or stemcell transplantation as part of a consolidation regimen. In someembodiments, the bone marrow or stem cell transplantation occurred atleast 3 months prior to treatment according to the methods providedherein. In some embodiments, the subject has undergone hydroxyureatreatment. In some embodiments, the hydroxyurea treatment occurred nolater than 24 hours prior to treatment according to the methods providedherein. In some embodiments, the subject has undergone prior inductionor consolidation therapy with cytarabine (Ara-C). In some embodiments,the subject has undergone treatment with systemic glucocorticosteroids.In some embodiments, the glucocorticosteroid treatment occurred no later24 hours prior to treatment according to the methods described herein.In other embodiments, the methods encompass treating subjects who havebeen previously treated for cancer, but are non-responsive to standardtherapies.

Also encompassed are methods of treating subjects having relapsed orrefractory leukemia. In some embodiments, the subject has been diagnosedwith a relapsed or refractory AML subtype, as defined by the WorldHealth Organization (WHO). Relapsed or refractory disease may be de novoAML or secondary AML, e.g., therapy-related AML (t-AML).

In some embodiments, the methods provided herein are used to treat drugresistant leukemias, such as chronic myelogenous leukemia (CML). Thus,treatment with a compound provided herein could provide an alternativefor patients who do not respond to other methods of treatment. In someembodiments, such other methods of treatment encompass treatment withGleevec® (imatinib mesylate). In some embodiments, provided herein aremethods of treatment of Philadelphia chromosome positive chronicmyelogenous leukemia (Ph+CML). In some embodiments, provided herein aremethods of treatment of Gleevec® (imatinib mesylate) resistantPhiladelphia chromosome positive chronic myelogenous leukemia (Ph+CML).

Also encompassed are methods of treating a subject regardless of thesubject's age, although some diseases or disorders are more common incertain age groups. In some embodiments, the subject is at least 18years old. In some embodiments, the subject is more than 18, 25, 35, 40,45, 50, 55, 60, 65, or 70 years old. In other embodiments, the subjectis less than 65 years old. In some embodiments, the subject is less than18 years old. In some embodiments, the subject is less than 18, 15, 12,10, 9, 8 or 7 years old.

In some embodiments, the methods may find use in subjects at least 50years of age, although younger subjects could benefit from the method aswell. In other embodiments, the subjects are at least 55, at least 60,at least 65, and at least 70 years of age. In another embodiment, thesubjects have adverse cytogenetics. “Adverse cytogenetics” is defined asany nondiploid karyotype, or greater than or equal to 3 chromosomalabnormalities. In another embodiment, the subjects are at least 60 yearsof age and have adverse cytogenetics. In another embodiment, thesubjects are 60-65 years of age and have adverse cytogenetics. Inanother embodiment, the subjects are 65-70 years of age and have adversecytogenetics.

In certain embodiments, the subject treated has no history of myocardialinfarction within three months of treatment according to the methodsprovided herein. In some embodiments, the subject has no history ofcerebrovascular accident or transient ischemic attack within threemonths of treatment according to the methods provided herein. In someembodiments, the subject has no suffered no thromboembelic event,including deep vein thrombosis or pulmonary embolus, within 28 days oftreatment according to the methods provided herein. In otherembodiments, the subject has not experienced or is not experiencinguncontrolled disseminated intravascular coagulation.

Because subjects with cancer have heterogeneous clinical manifestationsand varying clinical outcomes, the treatment given to a patient mayvary, depending on his/her prognosis. The skilled clinician will be ableto readily determine without undue experimentation specific secondaryagents, types of surgery, and types of non-drug based standard therapythat can be effectively used to treat an individual subject with cancer.

It will be appreciated that every suitable combination of the compoundsprovided herein with one or more of the aforementioned compounds andoptionally one or more further pharmacologically active substances iscontemplated herein.

E. Formulation of Pharmaceutical Compositions

The pharmaceutical compositions provided herein contain therapeuticallyeffective amounts of one or more of compounds provided herein and apharmaceutically acceptable carrier, diluent or excipient.

The compounds can be formulated into suitable pharmaceuticalpreparations such as solutions, suspensions, tablets, dispersibletablets, pills, capsules, powders, sustained release formulations orelixirs, for oral administration or in sterile solutions or suspensionsfor ophthalmic or parenteral administration, as well as transdermalpatch preparation and dry powder inhalers. Typically the compoundsdescribed above are formulated into pharmaceutical compositions usingtechniques and procedures well known in the art (see, e.g., AnselIntroduction to Pharmaceutical Dosage Forms, Seventh Edition 1999).

In the compositions, effective concentrations of one or more compoundsor pharmaceutically acceptable salts is (are) mixed with a suitablepharmaceutical carrier or vehicle. In certain embodiments, theconcentrations of the compounds in the compositions are effective fordelivery of an amount, upon administration, that treats, prevents, orameliorates one or more of the symptoms and/or progression of cancer,including solid tumors and blood borne tumors.

Typically, the compositions are formulated for single dosageadministration. To formulate a composition, the weight fraction ofcompound is dissolved, suspended, dispersed or otherwise mixed in aselected vehicle at an effective concentration such that the treatedcondition is relieved or ameliorated. Pharmaceutical carriers orvehicles suitable for administration of the compounds provided hereininclude any such carriers known to those skilled in the art to besuitable for the particular mode of administration.

In addition, the compounds may be formulated as the solepharmaceutically active ingredient in the composition or may be combinedwith other active ingredients. Liposomal suspensions, includingtissue-targeted liposomes, such as tumor-targeted liposomes, may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known to those skilled in the art. For example,liposome formulations may be prepared as known in the art. Briefly,liposomes such as multilamellar vesicles (MLV's) may be formed by dryingdown egg phosphatidyl choline and brain phosphatidyl serine (7:3 molarratio) on the inside of a flask. A solution of a compound providedherein in phosphate buffered saline lacking divalent cations (PBS) isadded and the flask shaken until the lipid film is dispersed. Theresulting vesicles are washed to remove unencapsulated compound,pelleted by centrifugation, and then resuspended in PBS.

The active compound is included in the pharmaceutically acceptablecarrier in an amount sufficient to exert a therapeutically useful effectin the absence of undesirable side effects on the patient treated. Thetherapeutically effective concentration may be determined empirically bytesting the compounds in in vitro and in vivo systems described hereinand then extrapolated therefrom for dosages for humans.

The concentration of active compound in the pharmaceutical compositionwill depend on absorption, tissue distribution, inactivation andexcretion rates of the active compound, the physicochemicalcharacteristics of the compound, the dosage schedule, and amountadministered as well as other factors known to those of skill in theart. For example, the amount that is delivered is sufficient toameliorate one or more of the symptoms of cancer, including solid tumorsand blood borne tumors.

In certain embodiments, a therapeutically effective dosage shouldproduce a serum concentration of active ingredient of from about 0.1ng/mL to about 50-100 μg/mL. In one embodiment, the pharmaceuticalcompositions provide a dosage of from about 0.001 mg to about 2000 mg ofcompound per kilogram of body weight per day. Pharmaceutical dosage unitforms are prepared to provide from about 1 mg to about 1000 mg and incertain embodiments, from about 10 to about 500 mg of the essentialactive ingredient or a combination of essential ingredients per dosageunit form.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuesmay also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed compositions.

Thus, effective concentrations or amounts of one or more of thecompounds described herein or pharmaceutically acceptable salts thereofare mixed with a suitable pharmaceutical carrier or vehicle forsystemic, topical or local administration to form pharmaceuticalcompositions. Compounds are included in an amount effective forameliorating one or more symptoms of, or for treating, retardingprogression, or preventing. The concentration of active compound in thecomposition will depend on absorption, tissue distribution,inactivation, excretion rates of the active compound, the dosageschedule, amount administered, particular formulation as well as otherfactors known to those of skill in the art.

The compositions are intended to be administered by a suitable route,including but not limited to orally, parenterally, rectally, topicallyand locally. For oral administration, capsules and tablets can beformulated. The compositions are in liquid, semi-liquid or solid formand are formulated in a manner suitable for each route ofadministration.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include any of the following components: asterile diluent, such as water for injection, saline solution, fixedoil, polyethylene glycol, glycerine, propylene glycol, dimethylacetamide or other synthetic solvent; antimicrobial agents, such asbenzyl alcohol and methyl parabens; antioxidants, such as ascorbic acidand sodium bisulfite; chelating agents, such asethylenediaminetetraacetic acid (EDTA); buffers, such as acetates,citrates and phosphates; and agents for the adjustment of tonicity suchas sodium chloride or dextrose. Parenteral preparations can be enclosedin ampules, pens, disposable syringes or single or multiple dose vialsmade of glass, plastic or other suitable material.

In instances in which the compounds exhibit insufficient solubility,methods for solubilizing compounds may be used. Such methods are knownto those of skill in this art, and include, but are not limited to,using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants,such as TWEEN®, or dissolution in aqueous sodium bicarbonate.

Upon mixing or addition of the compound(s), the resulting mixture may bea solution, suspension, emulsion or the like. The form of the resultingmixture depends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease, disorder or condition treatedand may be empirically determined.

The pharmaceutical compositions are provided for administration tohumans and animals in unit dosage forms, such as tablets, capsules,pills, powders, granules, sterile parenteral solutions or suspensions,and oral solutions or suspensions, and oil water emulsions containingsuitable quantities of the compounds or pharmaceutically acceptablesalts thereof. The pharmaceutically therapeutically active compounds andsalts thereof are formulated and administered in unit dosage forms ormultiple dosage forms. Unit dose forms as used herein refer tophysically discrete units suitable for human and animal subjects andpackaged individually as is known in the art. Each unit dose contains apredetermined quantity of the therapeutically active compound sufficientto produce the desired therapeutic effect, in association with therequired pharmaceutical carrier, vehicle or diluent. Examples of unitdose forms include ampules and syringes and individually packagedtablets or capsules. Unit dose forms may be administered in fractions ormultiples thereof. A multiple dose form is a plurality of identical unitdosage forms packaged in a single container to be administered insegregated unit dose form. Examples of multiple dose forms includevials, bottles of tablets or capsules or bottles of pints or gallons.Hence, multiple dose form is a multiple of unit doses which are notsegregated in packaging.

Sustained-release preparations can also be prepared. Suitable examplesof sustained-release preparations include semipermeable matrices ofsolid hydrophobic polymers containing the compound provided herein,which matrices are in the form of shaped articles, e.g., films, ormicrocapsule. Examples of sustained-release matrices includeiontophoresis patches, polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides,copolymers of L-glutamic acid and ethyl-L-glutamate, non-degradableethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymerssuch as the LUPRON DEPOT™ (injectable microspheres composed of lacticacid-glycolic acid copolymer and leuprolide acetate), andpoly-D-(−)-3-hydroxybutyric acid. While polymers such as ethylene-vinylacetate and lactic acid-glycolic acid enable release of molecules forover 100 days, certain hydrogels release proteins for shorter timeperiods. When encapsulated compound remain in the body for a long time,they may denature or aggregate as a result of exposure to moisture at37° C., resulting in a loss of biological activity and possible changesin their structure. Rational strategies can be devised for stabilizationdepending on the mechanism of action involved. For example, if theaggregation mechanism is discovered to be intermolecular S—S bondformation through thio-disulfide interchange, stabilization may beachieved by modifying sulfhydryl residues, lyophilizing from acidicsolutions, controlling moisture content, using appropriate additives,and developing specific polymer matrix compositions.

Dosage forms or compositions containing active ingredient in the rangeof 0.005% to 100% with the balance made up from non toxic carrier may beprepared. For oral administration, a pharmaceutically acceptable nontoxic composition is formed by the incorporation of any of the normallyemployed excipients, such as, for example pharmaceutical grades ofmannitol, lactose, starch, magnesium stearate, talcum, cellulosederivatives, sodium crosscarmellose, glucose, sucrose, magnesiumcarbonate or sodium saccharin. Such compositions include solutions,suspensions, tablets, capsules, powders and sustained releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers, such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid and others. Methodsfor preparation of these compositions are known to those skilled in theart. The contemplated compositions may contain about 0.001% 100% activeingredient, in certain embodiments, about 0.1 85% or about 75-95%.

The active compounds or pharmaceutically acceptable salts may beprepared with carriers that protect the compound against rapidelimination from the body, such as time release formulations orcoatings.

The compositions may include other active compounds to obtain desiredcombinations of properties. The compounds provided herein, orpharmaceutically acceptable salts thereof as described herein, may alsobe advantageously administered for therapeutic or prophylactic purposestogether with another pharmacological agent known in the general art tobe of value in treating one or more of the diseases or medicalconditions referred to hereinabove, such as diseases related tooxidative stress. It is to be understood that such combination therapyconstitutes a further aspect of the compositions and methods oftreatment provided herein.

Lactose-free compositions provided herein can contain excipients thatare well known in the art and are listed, for example, in the U.S.Pharmocopia (USP) SP (XXI)/NF (XVI). In general, lactose-freecompositions contain an active ingredient, a binder/filler, and alubricant in pharmaceutically compatible and pharmaceutically acceptableamounts. Exemplary lactose-free dosage forms contain an activeingredient, microcrystalline cellulose, pre-gelatinized starch andmagnesium stearate.

Further encompassed are anhydrous pharmaceutical compositions and dosageforms containing a compound provided herein. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen, Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, N.Y., NY, 1995, pp. 379-80. In effect,water and heat accelerate the decomposition of some compounds. Thus, theeffect of water on a formulation can be of great significance sincemoisture and/or humidity are commonly encountered during manufacture,handling, packaging, storage, shipment and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms provided hereincan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are anhydrous ifsubstantial contact with moisture and/or humidity during manufacturing,packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are packaged using materials known to prevent exposure towater such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs and strip packs.

E-1. Oral Dosage Forms

Oral pharmaceutical dosage forms are either solid, gel or liquid. Thesolid dosage forms are tablets, capsules, granules, and bulk powders.Types of oral tablets include compressed, chewable lozenges and tabletswhich may be enteric coated, sugar coated or film coated. Capsules maybe hard or soft gelatin capsules, while granules and powders may beprovided in non effervescent or effervescent form with the combinationof other ingredients known to those skilled in the art.

In certain embodiments, the formulations are solid dosage forms, such ascapsules or tablets. The tablets, pills, capsules, troches and the likecan contain any of the following ingredients, or compounds of a similarnature: a binder; a diluent; a disintegrating agent; a lubricant; aglidant; a sweetening agent; and a flavoring agent.

Examples of binders include microcrystalline cellulose, gum tragacanth,glucose solution, acacia mucilage, gelatin solution, sucrose and starchpaste. Lubricants include talc, starch, magnesium or calcium stearate,lycopodium and stearic acid. Diluents include, for example, lactose,sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.Glidants include, but are not limited to, colloidal silicon dioxide.Disintegrating agents include crosscarmellose sodium, sodium starchglycolate, alginic acid, corn starch, potato starch, bentonite,methylcellulose, agar and carboxymethylcellulose. Coloring agentsinclude, for example, any of the approved certified water soluble FD andC dyes, mixtures thereof; and water insoluble FD and C dyes suspended onalumina hydrate. Sweetening agents include sucrose, lactose, mannitoland artificial sweetening agents such as saccharin, and any number ofspray dried flavors. Flavoring agents include natural flavors extractedfrom plants such as fruits and synthetic blends of compounds whichproduce a pleasant sensation, such as, but not limited to peppermint andmethyl salicylate. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelaural ether. Emetic coatings include fatty acids, fats, waxes, shellac,ammoniated shellac and cellulose acetate phthalates. Film coatingsinclude hydroxyethylcellulose, sodium carboxymethylcellulose,polyethylene glycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the compound could be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action, such as antacids, H2 blockers, and diuretics. The activeingredient is a compound or pharmaceutically acceptable salt thereof asdescribed herein. Higher concentrations, up to about 98% by weight ofthe active ingredient may be included.

Pharmaceutically acceptable carriers included in tablets are binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, and wetting agents. Enteric coated tablets, because of theenteric coating, resist the action of stomach acid and dissolve ordisintegrate in the neutral or alkaline intestines. Sugar coated tabletsare compressed tablets to which different layers of pharmaceuticallyacceptable substances are applied. Film coated tablets are compressedtablets which have been coated with a polymer or other suitable coating.Multiple compressed tablets are compressed tablets made by more than onecompression cycle utilizing the pharmaceutically acceptable substancespreviously mentioned. Coloring agents may also be used in the abovedosage forms. Flavoring and sweetening agents are used in compressedtablets, sugar coated, multiple compressed and chewable tablets.Flavoring and sweetening agents are especially useful in the formationof chewable tablets and lozenges.

Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted from noneffervescent granules and effervescent preparations reconstituted fromeffervescent granules. Aqueous solutions include, for example, elixirsand syrups. Emulsions are either oil in-water or water in oil.

Elixirs are clear, sweetened, hydroalcoholic preparations.Pharmaceutically acceptable carriers used in elixirs include solvents.Syrups are concentrated aqueous solutions of a sugar, for example,sucrose, and may contain a preservative. An emulsion is a two phasesystem in which one liquid is dispersed in the form of small globulesthroughout another liquid. Pharmaceutically acceptable carriers used inemulsions are non aqueous liquids, emulsifying agents and preservatives.Suspensions use pharmaceutically acceptable suspending agents andpreservatives. Pharmaceutically acceptable substances used in noneffervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents. Pharmaceuticallyacceptable substances used in effervescent granules, to be reconstitutedinto a liquid oral dosage form, include organic acids and a source ofcarbon dioxide. Coloring and flavoring agents are used in all of theabove dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examplesof preservatives include glycerin, methyl and propylparaben, benzoicadd, sodium benzoate and alcohol. Examples of non aqueous liquidsutilized in emulsions include mineral oil and cottonseed oil. Examplesof emulsifying agents include gelatin, acacia, tragacanth, bentonite,and surfactants such as polyoxyethylene sorbitan monooleate. Suspendingagents include sodium carboxymethylcellulose, pectin, tragacanth, Veegumand acacia. Diluents include lactose and sucrose. Sweetening agentsinclude sucrose, syrups, glycerin and artificial sweetening agents suchas saccharin. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelauryl ether. Organic adds include citric and tartaric acid. Sources ofcarbon dioxide include sodium bicarbonate and sodium carbonate. Coloringagents include any of the approved certified water soluble FD and Cdyes, and mixtures thereof. Flavoring agents include natural flavorsextracted from plants such fruits, and synthetic blends of compoundswhich produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is encapsulated ina gelatin capsule. Such solutions, and the preparation and encapsulationthereof, are disclosed in U.S. Pat. Nos. 4,328,245; 4,409,239; and4,410,545. For a liquid dosage form, the solution, e.g., for example, ina polyethylene glycol, may be diluted with a sufficient quantity of apharmaceutically acceptable liquid carrier, e.g., water, to be easilymeasured for administration.

Alternatively, liquid or semi solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include, but are not limited to, those containing acompound provided herein, a dialkylated mono- or poly-alkylene glycol,including, but not limited to, 1,2-dimethoxymethane, diglyme, triglyme,tetraglyme, polyethylene glycol-350-dimethyl ether, polyethyleneglycol-550-dimethyl ether, polyethylene glycol-750-dimethyl etherwherein 350, 550 and 750 refer to the approximate average molecularweight of the polyethylene glycol, and one or more antioxidants, such asbutylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propylgallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, thiodipropionic acid and its esters, and dithiocarbamates.

Other formulations include, but are not limited to, aqueous alcoholicsolutions including a pharmaceutically acceptable acetal. Alcohols usedin these formulations are any pharmaceutically acceptable water-misciblesolvents having one or more hydroxyl groups, including, but not limitedto, propylene glycol and ethanol. Acetals include, but are not limitedto, di(lower alkyl) acetals of lower alkyl aldehydes such asacetaldehyde diethyl acetal.

In all embodiments, tablets and capsules formulations may be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient. Thus, for example, they may becoated with a conventional enterically digestible coating, such asphenylsalicylate, waxes and cellulose acetate phthalate.

E-2. Injectables, Solutions and Emulsions

Parenteral administration, generally characterized by injection, eithersubcutaneously, intramuscularly or intravenously is also contemplatedherein. Injectables can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, glycerol orethanol. In addition, if desired, the pharmaceutical compositions to beadministered may also contain minor amounts of non toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agents,stabilizers, solubility enhancers, and other such agents, such as forexample, sodium acetate, sorbitan monolaurate, triethanolamine oleateand cyclodextrins. Implantation of a slow release or sustained releasesystem, such that a constant level of dosage is maintained is alsocontemplated herein. Briefly, a compound provided herein is dispersed ina solid inner matrix, e.g., polymethylmethacrylate,polybutylmethacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethyleneterephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinylacetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinylalcohol and cross-linked partiallyhydrolyzed polyvinyl acetate, that is surrounded by an outer polymericmembrane, e.g., polyethylene, polypropylene, ethylene/propylenecopolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetatecopolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber,chlorinated polyethylene, polyvinylchloride, vinylchloride copolymerswith vinyl acetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble inbody fluids. The compound diffuses through the outer polymeric membranein a release rate controlling step. The percentage of active compoundcontained in such parenteral compositions is highly dependent on thespecific nature thereof, as well as the activity of the compound and theneeds of the subject.

Parenteral administration of the compositions includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as lyophilized powders, ready to becombined with a solvent just prior to use, including hypodermic tablets,sterile suspensions ready for injection, sterile dry insoluble productsready to be combined with a vehicle just prior to use and sterileemulsions. The solutions may be either aqueous or nonaqueous.

If administered intravenously, suitable carriers include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingthickening and solubilizing agents, such as glucose, polyethyleneglycol, and polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable carriers used in parenteral preparationsinclude aqueous vehicles, nonaqueous vehicles, antimicrobial agents,isotonic agents, buffers, antioxidants, local anesthetics, suspendingand dispersing agents, emulsifying agents, sequestering or chelatingagents and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations must be added to parenteral preparationspackaged in multiple dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propyl phydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcelluose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (TWEEN® 80). A sequestering or chelatingagent of metal ions include EDTA. Pharmaceutical carriers also includeethyl alcohol, polyethylene glycol and propylene glycol for watermiscible vehicles and sodium hydroxide, hydrochloric acid, citric acidor lactic acid for pH adjustment.

The concentration of the pharmaceutically active compound is adjusted sothat an injection provides an effective amount to produce the desiredpharmacological effect. The exact dose depends on the age, weight andcondition of the patient or animal as is known in the art.

The unit dose parenteral preparations are packaged in an ampule, a vialor a syringe with a needle. All preparations for parenteraladministration must be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterileaqueous solution containing an active compound is an effective mode ofadministration. Another embodiment is a sterile aqueous or oily solutionor suspension containing an active material injected as necessary toproduce the desired pharmacological effect.

Injectables are designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,such as more than 1% w/w of the active compound to the treatedtissue(s). The active ingredient may be administered at once, or may bedivided into a number of smaller doses to be administered at intervalsof time. It is understood that the precise dosage and duration oftreatment is a function of the tissue being treated and may bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the age of theindividual treated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of theformulations, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed formulations.

The compound may be suspended in micronized or other suitable form ormay be derivatized to produce a more soluble active product or toproduce a prodrug. The form of the resulting mixture depends upon anumber of factors, including the intended mode of administration and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration is sufficient for ameliorating the symptoms ofthe condition and may be empirically determined.

E-3. Lyophilized Powders

Of interest herein are also lyophilized powders, which can bereconstituted for administration as solutions, emulsions and othermixtures. They may also be reconstituted and formulated as solids orgels.

The sterile, lyophilized powder is prepared by dissolving a compoundprovided herein, or a pharmaceutically acceptable salt thereof, in asuitable solvent. The solvent may contain an excipient which improvesthe stability or other pharmacological component of the powder orreconstituted solution, prepared from the powder. Excipients that may beused include, but are not limited to, dextrose, sorbital, fructose, cornsyrup, xylitol, glycerin, glucose, sucrose or other suitable agent. Thesolvent may also contain a buffer, such as citrate, sodium or potassiumphosphate or other such buffer known to those of skill in the art at, inone embodiment, about neutral pH. Subsequent sterile filtration of thesolution followed by lyophilization under standard conditions known tothose of skill in the art provides the desired formulation. Generally,the resulting solution will be apportioned into vials forlyophilization. Each vial will contain a single dosage (including butnot limited to 10-1000 mg or 100-500 mg) or multiple dosages of thecompound. The lyophilized powder can be stored under appropriateconditions, such as at about 4° C. to room temperature.

Reconstitution of this lyophilized powder with water for injectionprovides a formulation for use in parenteral administration. Forreconstitution, about 1-50 mg, about 5-35 mg, or about 9-30 mg oflyophilized powder, is added per mL of sterile water or other suitablecarrier. The precise amount depends upon the selected compound. Suchamount can be empirically determined.

E-4. Topical Administration

Topical mixtures are prepared as described for the local and systemicadministration. The resulting mixture may be a solution, suspension,emulsion or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The compounds or pharmaceutically acceptable salts thereof may beformulated as aerosols for topical application, such as by inhalation(see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, whichdescribe aerosols for delivery of a steroid useful for treatment ofinflammatory diseases, particularly asthma). These formulations foradministration to the respiratory tract can be in the form of an aerosolor solution for a nebulizer, or as a microtine powder for insufflation,alone or in combination with an inert carrier such as lactose. In such acase, the particles of the formulation will have diameters of less than50 microns or less than 10 microns.

The compounds may be formulated for local or topical application, suchas for topical application to the skin and mucous membranes, such as inthe eye, in the form of gels, creams, and lotions and for application tothe eye or for intracisternal or intraspinal application. Topicaladministration is contemplated for transdermal delivery and also foradministration to the eyes or mucosa, or for inhalation therapies. Nasalsolutions of the active compound alone or in combination with otherpharmaceutically acceptable excipients can also be administered.

These solutions, particularly those intended for ophthalmic use, may beformulated as 0.01%-10% isotonic solutions, pH about 5-7, withappropriate salts.

E-5. Compositions for Other Routes of Administration

Other routes of administration, such as topical application, transdermalpatches, and rectal administration are also contemplated herein.

For example, pharmaceutical dosage forms for rectal administration arerectal suppositories, capsules and tablets for systemic effect. Rectalsuppositories are used herein mean solid bodies for insertion into therectum which melt or soften at body temperature releasing one or morepharmacologically or therapeutically active ingredients.Pharmaceutically acceptable substances utilized in rectal suppositoriesare bases or vehicles and agents to raise the melting point. Examples ofbases include cocoa butter (theobroma oil), glycerin gelatin, carbowax(polyoxyethylene glycol) and appropriate mixtures of mono, di andtriglycerides of fatty acids. Combinations of the various bases may beused. Agents to raise the melting point of suppositories includespermaceti and wax. Rectal suppositories may be prepared either by thecompressed method or by molding. An exemplary weight of a rectalsuppository is about 2 to 3 grams.

Tablets and capsules for rectal administration are manufactured usingthe same pharmaceutically acceptable substance and by the same methodsas for formulations for oral administration.

E-6. Sustained Release Compositions

Active ingredients provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and U.S. Pat. Nos. 4,008,719, 5,674,533, 5,059,595,5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480,5,733,566, 5,739,108, 5,891,474, 5,922,356, 5,972,891, 5,980,945,5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363,6,264,970, 6,267,981, 6,376,461, 6,419,961, 6,589,548, 6,613,358,6,699,500 and 6,740,634, each of which is incorporated herein byreference. Such dosage forms can be used to provide slow orcontrolled-release of one or more active ingredients using, for example,hydropropylmethyl cellulose, other polymer matrices, gels, permeablemembranes, osmotic systems, multilayer coatings, microparticles,liposomes, microspheres, or a combination thereof to provide the desiredrelease profile in varying proportions. Suitable controlled-releaseformulations known to those of ordinary skill in the art, includingthose described herein, can be readily selected for use with the activeingredients provided herein.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. In one embodiment, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. In certain embodiments,advantages of controlled-release formulations include extended activityof the drug, reduced dosage frequency, and increased patient compliance.In addition, controlled-release formulations can be used to affect thetime of onset of action or other characteristics, such as blood levelsof the drug, and can thus affect the occurrence of side (e.g., adverse)effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

In certain embodiments, the agent may be administered using intravenousinfusion, an implantable osmotic pump, a transdermal patch, liposomes,or other modes of administration. In one embodiment, a pump may be used(see, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald etal., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574(1989). In another embodiment, polymeric materials can be used. In yetanother embodiment, a controlled release system can be placed inproximity of the therapeutic target, i.e., thus requiring only afraction of the systemic dose (see, e.g., Goodson, Medical Applicationsof Controlled Release, vol. 2, pp. 115-138 (1984).

In some embodiments, a controlled release device is introduced into asubject in proximity of the site of inappropriate immune activation or atumor. Other controlled release systems are discussed in the review byLanger (Science 249:1527-1533 (1990). The active ingredient can bedispersed in a solid inner matrix, e.g., polymethylmethacrylate,polybutylmethacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethyleneterephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinylacetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinylalcohol and cross-linked partiallyhydrolyzed polyvinyl acetate, that is surrounded by an outer polymericmembrane, e.g., polyethylene, polypropylene, ethylene/propylenecopolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetatecopolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber,chlorinated polyethylene, polyvinylchloride, vinylchloride copolymerswith vinyl acetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble inbody fluids. The active ingredient then diffuses through the outerpolymeric membrane in a release rate controlling step. The percentage ofactive ingredient contained in such parenteral compositions is highlydependent on the specific nature thereof, as well as the needs of thesubject.

E-7. Targeted Formulations

The compounds provided herein, or pharmaceutically acceptable saltsthereof, may also be formulated to be targeted to a particular tissue,receptor, or other area of the body of the subject to be treated. Manysuch targeting methods are well known to those of skill in the art. Allsuch targeting methods are contemplated herein for use in the instantcompositions. For non-limiting examples of targeting methods, see, e.g.,U.S. Pat. Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865,6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975,6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and5,709,874.

In one embodiment, liposomal suspensions, including tissue-targetedliposomes, such as tumor-targeted liposomes, may also be suitable aspharmaceutically acceptable carriers. These may be prepared according tomethods known to those skilled in the art. For example, liposomeformulations may be prepared as described in U.S. Pat. No. 4,522,811.Briefly, liposomes such as multilamellar vesicles (MLV's) may be formedby drying down egg phosphatidyl choline and brain phosphatidyl serine(7:3 molar ratio) on the inside of a flask. A solution of a compoundprovided herein in phosphate buffered saline lacking divalent cations(PBS) is added and the flask shaken until the lipid film is dispersed.The resulting vesicles are washed to remove unencapsulated compound,pelleted by centrifugation, and then resuspended in PBS.

E-8. Articles of Manufacture

The compounds or pharmaceutically acceptable salts can be packaged asarticles of manufacture containing packaging material, a compound orpharmaceutically acceptable salt thereof provided herein, which is usedfor treatment, prevention or amelioration of one or more symptoms orprogression of cancer, including solid tumors and blood borne tumors,and a label that indicates that the compound or pharmaceuticallyacceptable salt thereof is used for treatment, prevention oramelioration of one or more symptoms or progression of cancer, includingsolid tumors and blood borne tumors.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products arewell known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packagingmaterials include, but are not limited to, blister packs, bottles,tubes, inhalers, pumps, bags, vials, containers, syringes, pens,bottles, and any packaging material suitable for a selected formulationand intended mode of administration and treatment. A wide array offormulations of the compounds and compositions provided herein arecontemplated.

F. Evaluation of the Activity of the Compounds

Standard physiological, pharmacological and biochemical procedures areavailable for testing the compounds to identify those that possess thedesired anti-proliferative activity.

Such assays include, for example, biochemical assays such as bindingassays, radioactivity incorporation assays, as well as a variety of cellbased assays.

G. Preparation of Compounds

The compounds provided herein can be prepared by methods known to one ofskill in the art and following procedures similar to those described inthe Examples section herein and routine modifications thereof.

An exemplary reaction scheme for the preparation of compounds isillustrated below.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative, and are not to be takenas limitations upon the scope of the subject matter. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse provided herein, may be made without departing from the spirit andscope thereof. U.S. patents and publications referenced herein areincorporated by reference.

6. EXAMPLES

Certain embodiments of the invention are illustrated by the followingnon-limiting example.

Example 1 Synthesis ofN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methoxyphenyl)acetamide

Methyl 4-bromo-2-methylbenzoate

4-Bromo-2-methylbenzoic acid (100 g, 465.02 mmol), concentrated sulfuricacid (52 mL) in methanol (1 L) were combined and heated to 65° C. for 18h. The reaction was concentrated and the residue diluted with ethylacetate (500 mL), washed with saturated sodium bicarbonate solution (150mL), water (200 mL), brine (250 mL) and dried over sodium sulfate. Theorganic phase was concentrated under reduced pressure and further driedunder high vacuum to give methyl 4-bromo-2-methylbenzoate (102 g, 445.27mmol, 95% yield) as a red liquid. 1H NMR (400 MHz, Chloroform-d₁) δ 7.78(d, J=8.3 Hz, 1H), 7.45-7.30 (m, 2H), 3.88 (s, 3H), 2.57 (s, 3H).

Methyl-4-bromo-2-(bromomethyl) benzoate

Methyl 4-bromo-2-methylbenzoate (102 g, 445.27 mmol), NBS (79.2 g,445.27 mmol), Azo-isobutyronitrile (2.58 g, 16 mmol) in acetonitrile(600 mL) were combined and refluxed at 85° C. for 18 h. The mixture wasconcentrated, and to the residue was added dichloromethane (150 mL). Theresultant solid was removed by filtration. The filtrate was concentratedand purified by flash column chromatography (0-4% EtOAc in Hexanes).Fractions containing product was concentrated under reduced pressure andfurther dried under high vacuum to give Methyl-4-bromo-2-(bromomethyl)benzoate (100 g, 324.70 mmol, 72.9% yield) as an off-white solid. 1H NMR(300 MHz, Dimethylsulfoxide-d₆) δ 7.88 (d, J=2.2 Hz, 1H), 7.82 (dd,J=8.4, 2.1 Hz, 1H), 7.72-7.64 (m, 1H), 5.00 (s, 2H), 3.88 (s, 3H).

3-(5-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Methyl-4-bromo-2-(bromomethyl) benzoate (100 g, 324.70 mmol),3-Aminopiperidine-2,6-dione.hydrochloride (53.2 g, 324.70 mmol),triethylamine (113.29 mL, 811.75 mmol), and dry dimethylformamide (400mL) were combined and stirred at room temperature under inert atmospherefor 18 h. The reaction was cooled to 5° C. and diluted with water (400mL), acetic acid (115 mL), diethylether (300 mL) with continued stirringat room temperature for 2 h. The resultant solid was filtered, washedwith ether (100 mL) and further dried under high vacuum to give3-(5-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (46 g, 142.35 mmol,43.8% yield) as a light blue solid. MS (ESI) m/z 325.0 [M+1]⁺.

2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile

3-(5-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (46 g, 142.35mmol), 1,1′-Bis(diphenylphosphino)ferrocene (788 mg, 1.423 mmol), zinccyanide (25 g, 213.52 mmol), zinc acetate (7.83 g, 42.7 mmol) and drydimethylformamide (360 mL) were combined and degassed before addition oftris(dibenzylideneacetone)dipalladium(0) (0.364 g, 0.398 mmol). Themixtures was evacuated and replaced with argon 3 times, then stirred at120° C. for 20 h. The mixture was cooled to room temperature, filteredand purified by silica column chromatography (0-5% methanol indichloromethane). Fractions containing product were combined and solventremoved under reduced pressure and then further dried under high vacuumto give 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile (22g, 81.78 mmol, 57.2% yield) as a brown solid. MS (ESI) m/z 268.0

3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile (10 g, 37.13mmol), methanesulfonic acid (2.6 mL, 40.85 mmol), 10% dry Palladium oncarbon (4 g) and dimethylacetamide (320 mL) were combined and shaken ina hydrogenation vessel and kept under 50 Psi at 40° C. for 20 h. Thehydrogen atmosphere was evacuated and the mixture was filtered through acelite pad, washed with water (100 mL), and concentrated. To theresulting residue was added 1% methanol-dichloromethane which uponfiltration and drying under high vacuum gave3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (5.6 g,15.17 mmol, 40% yield) as an off-white solid. MS (ESI) m/z 272.0 [M−1].

N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methoxyphenyl)acetamide

To 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionemethanesulfonate (0.200 g, 0.541 mmol) in DMF (3 mL) was added HATU(0.226 g, 0.596 mmol), 2,2-difluoro-2-(4-methoxyphenyl)acetic acid(0.109 g, 0.541 mmol) followed by N-ethyl-N-isopropylpropan-2-amine(0.262 mL, 1.624 mmol). Let stir at 25° C. for 16 h. Added 30 mL ofwater and filtered. Rinsed with EtOAc, dried under vacuum to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methoxyphenyl)acetamide(0.080 g, 0.175 mmol, 32.3% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 10.98 (s, 1H) 9.57 (t, J=6.15 Hz, 1H) 7.69 (d, J=7.88 Hz,1H) 7.48-7.57 (m, 2H) 7.34-7.45 (m, 2H) 7.07 (m, J=8.83 Hz, 2H) 5.11(dd, J=13.24, 5.36 Hz, 1H) 4.38-4.50 (m, 3H) 4.23-4.36 (m, 1H) 3.81 (s,3H) 2.85-2.98 (m, 1H) 2.56-2.68 (m, 1H) 2.39 (dd, J=12.93, 4.73 Hz, 1H)1.95-2.07 (m, 1H). MS (ESI) m/z 458.2 [M+1]⁺.

Example 2 Synthesis of2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionemethanesulfonate (0.200 g, 0.541 mmol) in DMF (3 mL) was added HATU(0.226 g, 0.596 mmol), 2-(3-chlorophenyl)-2,2-difluoroacetic acid (0.112g, 0.541 mmol) followed by N-ethyl-N-isopropylpropan-2-amine (0.262 mL,1.624 mmol). Let stir at 25° C. for 16 h. Added 30 mL of water andfiltered. Rinsed with EtOAc, dried under vacuum to afford2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(0.090 g, 0.195 mmol, 36.0% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 10.98 (s, 1H) 9.70 (t, J=5.99 Hz, 1H) 7.53-7.71 (m, 5H)7.32-7.45 (m, 2H) 5.11 (dd, J=13.40, 5.20 Hz, 1H) 4.39-4.51 (m, 3H)4.25-4.38 (m, 1H) 2.85-2.99 (m, 1H) 2.55-2.68 (m, 1H) 2.40 (dd, J=13.08,4.57 Hz, 1H) 1.95-2.05 (m, 1H). MS (ESI) m/z 462.2 [M+1]⁺.

Example 3 Synthesis ofN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluorophenyl)acetamide

N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluorophenyl)acetamide

To 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionemethanesulfonate (0.200 g, 0.541 mmol) in DMF (3 mL) was added HATU(0.226 g, 0.596 mmol), 2,2-difluoro-2-(4-fluorophenyl)acetic acid (0.103g, 0.541 mmol) followed by N-ethyl-N-isopropylpropan-2-amine (0.262 mL,1.624 mmol). Let stir at 25° C. for 16 h. Added 30 mL of water andfiltered. Rinsed with EtOAc, dried under vacuum to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluorophenyl)acetamide(0.100 g, 0.225 mmol, 41.5% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 10.98 (br. s., 1H) 9.66 (t, J=5.99 Hz, 1H) 7.58-7.73 (m,3H) 7.29-7.47 (m, 4H) 5.11 (dd, J=13.40, 5.20 Hz, 1H) 4.38-4.53 (m, 3H)4.24-4.36 (m, 1H) 2.81-3.00 (m, 1H) 2.56-2.67 (m, 1H) 2.40 (qd, J=13.19,4.57 Hz, 1H) 1.91-2.07 (m, 1H).

Example 4 Synthesis ofN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(p-tolyl)acetamide

N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(p-tolyl)acetamide

To 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionemethanesulfonate (0.200 g, 0.541 mmol) in DMF (3 mL) was added HATU(0.226 g, 0.596 mmol), 2,2-difluoro-2-(p-tolyl)acetic acid (0.101 g,0.541 mmol) followed by N-ethyl-N-isopropylpropan-2-amine (0.262 mL,1.624 mmol). Let stir at 25° C. for 16 h. Added 30 mL of water andfiltered. Rinsed with EtOAc, dried under vacuum to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(p-tolyl)acetamide(0.110 g, 0.249 mmol, 46.0% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 10.98 (s, 1H) 9.59 (t, J=6.15 Hz, 1H) 7.68 (d, J=7.88 Hz,1H) 7.48 (d, J=8.20 Hz, 2H) 7.26-7.43 (m, 4H) 5.11 (dd, J=13.24, 5.04Hz, 1H) 4.37-4.50 (m, 3H) 4.22-4.34 (m, 1H) 2.84-2.99 (m, 1H) 2.56-2.67(m, 1H) 2.31-2.45 (m, 4H) 1.93-2.07 (m, 1H). MS (ESI) m/z 442.2 [M+1]⁺.

Example 5 Synthesis of2-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

2-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionemethanesulfonate (0.200 g, 0.541 mmol) in DMF (3 mL) was added HATU(0.226 g, 0.596 mmol), 2-(3,4-dichlorophenyl)-2,2-difluoroacetic acid(0.130 g, 0.541 mmol) followed by N-ethyl-N-isopropylpropan-2-amine(0.262 mL, 1.624 mmol). Let stir at 25° C. for 16 h. Added 30 mL ofwater and filtered. Rinsed with EtOAc, dried under vacuum to afford2-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(0.110 g, 0.222 mmol, 40.9% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 10.98 (s, 1H) 9.71 (t, J=5.99 Hz, 1H) 7.79-7.88 (m, 2H)7.69 (d, J=7.88 Hz, 1H) 7.59 (dd, J=8.51, 2.21 Hz, 1H) 7.43 (s, 1H) 7.38(d, J=7.88 Hz, 1H) 5.11 (dd, J=13.08, 5.20 Hz, 1H) 4.39-4.51 (m, 3H)4.26-4.37 (m, 1H) 2.86-2.98 (m, 1H) 2.61 (d, J=18.92 Hz, 1H) 2.39 (dd,J=13.40, 4.89 Hz, 1H) 1.95-2.06 (m, 1H). MS (ESI) m/z 498.0 [M+1]⁺.

Example 6 Synthesis of2-(2-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

2-(2-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionemethanesulfonate (0.200 g, 0.541 mmol) in DMF (3 mL) was added HATU(0.226 g, 0.596 mmol), 2-(2-chlorophenyl)-2,2-difluoroacetic acid (0.112g, 0.541 mmol) followed by N-ethyl-N-isopropylpropan-2-amine (0.262 mL,1.624 mmol). Let stir at 25° C. for 16 h. Added 30 mL of water andfiltered. Rinsed with EtOAc, dried under vacuum to afford2-(2-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(0.090 g, 0.195 mmol, 36.0% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 10.98 (s, 1H) 9.68 (t, J=6.31 Hz, 1H) 7.68-7.79 (m, 2H)7.56-7.63 (m, 2H) 7.49-7.56 (m, 2H) 7.46 (d, J=7.88 Hz, 1H) 5.12 (dd,J=13.24, 5.36 Hz, 1H) 4.40-4.56 (m, 3H) 4.27-4.38 (m, 1H) 2.92 (ddd,J=17.50, 13.71, 5.36 Hz, 1H) 2.61 (d, J=16.71 Hz, 1H) 2.32-2.46 (m, 1H)1.94-2.10 (m, 1H). MS (ESI) m/z 462.0 [M+1]⁺.

Example 7 Synthesis of2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionemethanesulfonate (0.200 g, 0.541 mmol) in DMF (3 mL) was added HATU(0.226 g, 0.596 mmol), 2-(4-chlorophenyl)-2,2-difluoroacetic acid (0.112g, 0.541 mmol) followed by N-ethyl-N-isopropylpropan-2-amine (0.262 mL,1.624 mmol). Let stir at 25° C. for 16 h. Added 30 mL of water andfiltered. Rinsed with EtOAc, dried under vacuum to afford2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(0.080 g, 0.173 mmol, 32.0% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 10.98 (s, 1H) 9.68 (t, J=6.15 Hz, 1H) 7.69 (d, J=7.88 Hz,1H) 7.58-7.66 (m, 4H) 7.33-7.44 (m, 2H) 5.11 (dd, J=13.24, 5.04 Hz, 1H)4.39-4.50 (m, 3H) 4.24-4.35 (m, 1H) 2.85-2.98 (m, 1H) 2.61 (dd, J=15.29,2.05 Hz, 1H) 2.39 (dd, J=12.93, 4.73 Hz, 1H) 1.95-2.07 (m, 1H). MS (ESI)m/z 462.0 [M+1]⁺.

Example 8 Synthesis ofN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(trifluoromethyl)phenyl)acetamide

N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(trifluoromethyl)phenyl)acetamide

To 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionemethanesulfonate (0.200 g, 0.541 mmol) in DMF (3 mL) was added HATU(0.226 g, 0.596 mmol), 2,2-difluoro-2-(2-(trifluoromethyl)phenyl)aceticacid (0.130 g, 0.541 mmol) followed by N-ethyl-N-isopropylpropan-2-amine(0.262 mL, 1.624 mmol). Let stir at 25° C. for 16 h. Added 30 mL ofwater and filtered. Rinsed with EtOAc, dried under vacuum to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(trifluoromethyl)phenyl)acetamide(0.080 g, 0.161 mmol, 29.8% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 10.98 (s, 1H) 9.70 (t, J=6.15 Hz, 1H) 7.66-7.81 (m, 3H)7.47-7.59 (m, 3H) 7.44 (d, J=8.51 Hz, 1H) 5.12 (dd, J=13.40, 5.20 Hz,1H) 4.40-4.54 (m, 3H) 4.27-4.38 (m, 1H) 2.85-3.00 (m, 1H) 2.57-2.67 (m,1H) 2.35-2.45 (m, 1H) 1.94-2.07 (m, 1H).

Example 9 Synthesis of2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionemethanesulfonate (0.200 g, 0.541 mmol) in DMF (3 mL) was added HATU(0.226 g, 0.596 mmol), 2-(4-(tert-butyl)phenyl)-2,2-difluoroacetic acid(0.124 g, 0.541 mmol) followed by N-ethyl-N-isopropylpropan-2-amine(0.262 mL, 1.624 mmol). Let stir at 25° C. for 16 h. Added 30 mL ofwater and filtered. Rinsed with EtOAc, dried under vacuum to afford2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(0.095 g, 0.196 mmol, 36.3% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 10.98 (s, 1H) 9.61 (t, J=5.99 Hz, 1H) 7.68 (d, J=7.88 Hz,1H) 7.49-7.60 (m, 4H) 7.33-7.44 (m, 2H) 5.11 (dd, J=13.24, 5.04 Hz, 1H)4.37-4.50 (m, 3H) 4.24-4.35 (m, 1H) 2.86-2.98 (m, 1H) 2.57-2.67 (m, 1H)2.38 (dd, J=13.40, 4.57 Hz, 1H) 1.92-2.06 (m, 1H) 1.22-1.36 (m, 9H). MS(ESI) m/z 484.0 [M+1]⁺.

Example 10 Synthesis ofN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-phenylacetamide

A.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-phenylacetamide

3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Mesylicacid (0.050 g, 0.135 mmol) was placed in a vial withN,N-dimethylformamide (1.0 mL), 2,2-difluoro-2-phenylacetic acid (0.023g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixturewas stirred at room temperature for 18 h. The reaction mixture was takenup in dimethylsulfoxide and purified using reverse-phase semipreparatory HPLC (5-100% acetonitrile+0.1% formic acid in water+0.1%formic acid, over 20 min). Fractions containing desired product werecombined and volatile organics were removed under reduced pressure togiveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-phenylacetamide(0.039 g, 0.091 mmol, 67.4% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.00 (s, 1H), 9.67 (t, J=6.25 Hz, 1H), 7.67 (d, J=7.81 Hz,1H), 7.50-7.62 (m, 5H), 7.34-7.42 (m, 2H), 5.11 (dd, J=5.08, 13.28 Hz,1H), 4.38-4.47 (m, 3H), 4.24-4.31 (m, 1H), 2.86-2.97 (m, 1H), 2.55-2.64(m, 1H), 2.32-2.45 (m, 1H), 1.99 (dtd, J=2.34, 5.25, 12.55 Hz, 1H). MS(ESI) m/z 428.2 [M+1]⁺.

Example 11 Synthesis of2-(3-chloro-4-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A.2-(3-chloro-4-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Mesylicacid (0.050 g, 0.135 mmol) was placed in a vial withN,N-Dimethylformamide (1.0 mL),2-(3-chloro-4-fluorophenyl)-2,2-difluoroacetic acid (0.030 g, 0.135mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixturewas stirred at room temperature for 18 h. The reaction mixture was takenup in dimethylsulfoxide and purified using reverse-phase semipreparatory HPLC (5-100% acetonitrile+0.1% formic acid in water+0.1%formic acid, over 20 min). Fractions containing desired product werecombined and volatile organics were removed under reduced pressure togive2-(3-chloro-4-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamideas a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H), 9.72 (t,J=6.05 Hz, 1H), 7.81 (dd, J=1.76, 7.23 Hz, 1H), 7.69 (d, J=7.81 Hz, 1H),7.58-7.65 (m, 2H), 7.43 (s, 1H), 7.35-7.39 (m, 1H), 5.11 (dd, J=5.08,13.28 Hz, 1H), 4.40-4.48 (m, 3H), 4.26-4.34 (m, 1H), 2.92 (ddd, J=5.47,13.77, 17.48 Hz, 1H), 2.56-2.64 (m, 1H), 2.31-2.45 (m, 1H), 1.95-2.04(m, 1H). MS (ESI) m/z 480.0 [M+1]⁺.

Example 12 Synthesis of2-(2,6-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A.2-(2,6-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Mesylicacid (0.050 g, 0.135 mmol) was placed in a vial withN,N-Dimethylformamide (1.0 mL),2-(2,6-difluorophenyl)-2,2-difluoroacetic acid (0.028 g, 0.135 mmol),diisopropylethylamine (0.071 mL, 0.406 mmol), and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixturewas stirred at room temperature for 18 h. The reaction mixture was takenup in dimethylsulfoxide and purified using reverse-phase semipreparatory HPLC (5-100% acetonitrile+0.1% formic acid in water+0.1%formic acid, over 20 min). Fractions containing desired product werecombined and volatile organics were removed under reduced pressure togive2-(2,6-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(0.039 g, 0.084 mmol, 62.2% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.98 (s, 1H), 9.73 (t, J=5.99 Hz, 1H), 7.65-7.73 (m, 2H),7.49 (s, 1H), 7.43 (d, J=7.88 Hz, 1H), 7.27 (dd, J=8.67, 9.62 Hz, 2H),5.11 (dd, J=5.20, 13.40 Hz, 1H), 4.50 (d, J=5.99 Hz, 2H), 4.46 (d,J=17.34 Hz, 1H), 4.29-4.35 (m, 1H), 2.91 (ddd, J=5.36, 13.71, 17.50 Hz,1H), 2.57-2.63 (m, 1H), 2.40 (qd, J=4.57, 13.19 Hz, 1H), 2.01 (dtd,J=2.36, 5.26, 12.65 Hz, 1H). MS (ESI) m/z 464.2 [M+1]⁺.

Example 13 Synthesis of2-(5-chloro-2-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A.2-(5-chloro-2-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Mesylicacid (0.050 g, 0.135 mmol) was placed in a vial withN,N-Dimethylformamide (1.0 mL),2-(5-chloro-2-methoxyphenyl)-2,2-difluoroacetic acid (0.032 g, 0.135mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixturewas stirred at room temperature for 18 h. The reaction mixture was takenup in dimethylsulfoxide and purified using reverse-phase semipreparatory HPLC (5-100% acetonitrile+0.1% formic acid in water+0.1%formic acid, over 20 min). Fractions containing desired product werecombined and volatile organics were removed under reduced pressure togive2-(5-chloro-2-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(0.044 g, 0.089 mmol, 66.1% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.97 (s, 1H), 9.41 (t, J=5.99 Hz, 1H), 7.73 (d, J=7.88 Hz,1H), 7.59 (dd, J=2.84, 8.83 Hz, 1H), 7.53 (d, J=2.52 Hz, 1H), 7.48 (s,1H), 7.43 (d, J=7.57 Hz, 1H), 7.17 (d, J=8.83 Hz, 1H), 5.11 (dd, J=5.20,13.40 Hz, 1H), 4.43-4.49 (m, 3H), 4.29-4.35 (m, 1H), 3.68 (s, 3H), 2.91(ddd, J=5.36, 13.71, 17.50 Hz, 1H), 2.57-2.63 (m, 1H), 2.40 (qd, J=4.26,13.08 Hz, 1H), 2.00 (dtd, J=2.52, 5.32, 12.69 Hz, 1H). MS (ESI) m/z492.2 [M+1]⁺.

Example 14 Synthesis ofN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-fluoro-2-methoxyphenyl)acetamide

A.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-fluoro-2-methoxyphenyl)acetamide

3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Mesylicacid (0.050 g, 0.135 mmol) was placed in a vial withN,N-Dimethylformamide (1.0 mL),2,2-difluoro-2-(5-fluoro-2-methoxyphenyl)acetic acid (0.030 g, 0.135mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixturewas stirred at room temperature for 18 h. The reaction mixture was takenup in dimethylsulfoxide and purified using reverse-phase semipreparatory HPLC (5-100% acetonitrile+0.1% formic acid in water+0.1%formic acid, over 20 min). Fractions containing desired product werecombined and volatile organics were removed under reduced pressure togiveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-fluoro-2-methoxyphenyl)acetamide(0.043 g, 0.090 mmol, 66.8% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.97 (s, 1H), 9.40 (t, J=5.99 Hz, 1H), 7.73 (d, J=7.57 Hz,1H), 7.49 (s, 1H), 7.44 (d, J=7.88 Hz, 1H), 7.36-7.41 (m, 2H), 7.13-7.18(m, 1H), 5.11 (dd, J=5.20, 13.40 Hz, 1H), 4.43-4.50 (m, 3H), 4.29-4.35(m, 1H), 3.65 (s, 3H), 2.92 (ddd, J=5.52, 13.64, 17.42 Hz, 1H),2.57-2.63 (m, 1H), 2.40 (qd, J=4.10, 13.24 Hz, 1H), 2.01 (dtd, J=2.21,5.34, 12.65 Hz, 1H). MS (ESI) m/z 476.0 [M+1]⁺.

Example 15 Synthesis ofN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(o-tolyl)acetamide

A.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(o-tolyl)acetamide

3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Mesylicacid (0.050 g, 0.135 mmol) was placed in a vial withN,N-Dimethylformamide (1.0 mL), 2,2-difluoro-2-(o-tolyl)acetic acid(0.025 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixturewas stirred at room temperature for 18 h. The reaction mixture was takenup in dimethylsulfoxide and purified using reverse-phase semipreparatory HPLC (5-100% acetonitrile+0.1% formic acid in water+0.1%formic acid, over 20 min). Fractions containing desired product werecombined and volatile organics were removed under reduced pressure togiveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(o-tolyl)acetamide(0.038 g, 0.086 mmol, 63.6% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.97 (s, 1H), 9.59 (t, J=5.99 Hz, 1H), 7.69 (d, J=8.20 Hz,1H), 7.50-7.53 (m, 1H), 7.39-7.46 (m, 3H), 7.28-7.34 (m, 2H), 5.10 (dd,J=5.36, 13.24 Hz, 1H), 4.41-4.49 (m, 3H), 4.27-4.33 (m, 1H), 2.87-2.95(m, 1H), 2.57-2.63 (m, 1H), 2.39 (qd, J=4.41, 13.24 Hz, 1H), 2.33 (s,3H), 2.00 (dtd, J=2.21, 5.32, 12.69 Hz, 1H). MS (ESI) m/z 442.2 [M+1]⁺.

Example 16 Synthesis of2-(4-(2-(dimethylamino)-2-oxoethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A.2-(4-(2-(dimethylamino)-2-oxoethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Mesylicacid (0.050 g, 0.135 mmol) was placed in a vial withN,N-Dimethylformamide (1.0 mL),2-(4-(2-(dimethylamino)-2-oxoethoxy)phenyl)-2,2-difluoroacetic acid(0.037 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixturewas stirred at room temperature for 18 h. The reaction mixture was takenup in dimethylsulfoxide and purified using reverse-phase semipreparatory HPLC (5-100% acetonitrile+0.1% formic acid in water+0.1%formic acid, over 20 min). Fractions containing desired product werecombined and volatile organics were removed under reduced pressure togive2-(4-(2-(dimethylamino)-2-oxoethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(0.021 g, 0.040 mmol, 29.4% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.97 (s, 1H), 9.56 (t, J=6.15 Hz, 1H), 7.67 (dd, J=0.63,7.57 Hz, 1H), 7.46-7.50 (m, 2H), 7.35-7.38 (m, 2H), 7.00-7.04 (m, 2H),5.10 (dd, J=5.20, 13.40 Hz, 1H), 4.89 (s, 2H), 4.39-4.46 (m, 3H),4.26-4.31 (m, 1H), 2.99 (s, 3H), 2.87-2.95 (m, 1H), 2.84 (s, 3H),2.57-2.62 (m, 1H), 2.33-2.43 (m, 1H), 2.00 (dtd, J=2.36, 5.18, 12.49 Hz,1H). MS (ESI) m/z 529.2 [M+1]⁺.

Example 17 Synthesis of2-(2,5-dimethoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A.2-(2,5-dimethoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Mesylicacid (0.050 g, 0.135 mmol) was placed in a vial withN,N-Dimethylformamide (1.0 mL),2-(2,5-dimethoxyphenyl)-2,2-difluoroacetic acid (0.031 g, 0.135 mmol),diisopropylethylamine (0.071 mL, 0.406 mmol), and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixturewas stirred at room temperature for 18 h. The reaction mixture was takenup in dimethylsulfoxide and purified using reverse-phase semipreparatory HPLC (5-100% acetonitrile+0.1% formic acid in water+0.1%formic acid, over 20 min). Fractions containing desired product werecombined and volatile organics were removed under reduced pressure togive2-(2,5-dimethoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(0.043 g, 0.088 mmol, 65.2% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.97 (s, 1H), 9.33 (t, J=5.99 Hz, 1H), 7.72 (d, J=7.88 Hz,1H), 7.49 (s, 1H), 7.42-7.46 (m, 1H), 7.04-7.10 (m, 3H), 5.11 (dd,J=5.20, 13.40 Hz, 1H), 4.43-4.49 (m, 3H), 4.29-4.35 (m, 1H), 3.75 (s,3H), 3.61 (s, 3H), 2.91 (ddd, J=5.52, 13.56, 17.50 Hz, 1H), 2.57-2.64(m, 1H), 2.40 (qd, J=4.73, 13.24 Hz, 1H), 2.00 (dtd, J=2.36, 5.30, 12.57Hz, 1H). MS (ESI) m/z 488.2 [M+1]⁺.

Example 18 Synthesis ofN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-fluorophenyl)acetamide

A.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-fluorophenyl)acetamide

3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Mesylicacid (0.050 g, 0.135 mmol) was placed in a vial withN,N-Dimethylformamide (1.0 mL), 2,2-difluoro-2-(2-fluorophenyl)aceticacid (0.026 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406mmol), and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixturewas stirred at room temperature for 18 h. The reaction mixture was takenup in dimethylsulfoxide and purified using reverse-phase semipreparatory HPLC (5-100% acetonitrile+0.1% formic acid in water+0.1%formic acid, over 20 min). Fractions containing desired product werecombined and volatile organics were removed under reduced pressure togiveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-fluorophenyl)acetamide(0.030 g, 0.067 mmol, 49.8% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.97 (s, 1H), 9.69 (t, J=6.15 Hz, 1H), 7.70 (d, J=8.20 Hz,1H), 7.61-7.67 (m, 2H), 7.47 (s, 1H), 7.40-7.44 (m, 1H), 7.34-7.40 (m,2H), 5.11 (dd, J=5.20, 13.40 Hz, 1H), 4.50 (d, J=6.31 Hz, 2H), 4.45 (d,J=17.34 Hz, 1H), 4.29-4.34 (m, 1H), 2.91 (ddd, J=5.52, 13.64, 17.42 Hz,1H), 2.57-2.63 (m, 1H), 2.40 (qd, J=4.73, 13.24 Hz, 1H), 2.01 (dtd,J=2.36, 5.26, 12.65 Hz, 1H). MS (ESI) m/z 446.2 [M+1]⁺.

Example 19 Synthesis ofN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxyphenyl)-2,2-difluoroacetamide

A.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxyphenyl)-2,2-difluoroacetamide

3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Mesylicacid (0.050 g, 0.135 mmol) was placed in a vial withN,N-Dimethylformamide (1.0 mL), 2-(2-ethoxyphenyl)-2,2-difluoroaceticacid (0.029 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406mmol), and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixturewas stirred at room temperature for 18 h. The reaction mixture was takenup in dimethylsulfoxide and purified using reverse-phase semipreparatory HPLC (5-100% acetonitrile+0.1% formic acid in water+0.1%formic acid, over 20 min). Fractions containing desired product werecombined and volatile organics were removed under reduced pressure togiveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxyphenyl)-2,2-difluoroacetamide(0.045 g, 0.095 mmol, 70.5% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.97 (s, 1H), 9.31 (t, J=6.15 Hz, 1H), 7.70 (d, J=7.88 Hz,1H), 7.55 (dd, J=1.58, 7.57 Hz, 1H), 7.47-7.52 (m, 2H), 7.45 (d, J=8.51Hz, 1H), 7.11 (d, J=8.20 Hz, 1H), 7.05 (td, J=0.79, 7.49 Hz, 1H), 5.11(dd, J=5.20, 13.40 Hz, 1H), 4.42-4.48 (m, 3H), 4.28-4.34 (m, 1H), 3.99(q, J=6.94 Hz, 2H), 2.87-2.96 (m, 1H), 2.57-2.63 (m, 1H), 2.40 (qd,J=4.41, 13.24 Hz, 1H), 2.00 (dtd, J=2.21, 5.08, 12.53 Hz, 1H), 1.13 (t,J=6.94 Hz, 3H). MS (ESI) m/z 472.2 [M+1]⁺.

Example 20 Synthesis ofN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(trifluoromethoxy)phenyl)acetamide

A.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(trifluoromethoxy)phenyl)acetamide

3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Mesylicacid (0.050 g, 0.135 mmol) was placed in a vial withN,N-Dimethylformamide (1.0 mL),2,2-difluoro-2-(2-(trifluoromethoxy)phenyl)acetic acid (0.035 g, 0.135mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixturewas stirred at room temperature for 18 h. The reaction mixture was takenup in dimethylsulfoxide and purified using reverse-phase semipreparatory HPLC (5-100% acetonitrile+0.1% formic acid in water+0.1%formic acid, over 20 min). Fractions containing desired product werecombined and volatile organics were removed under reduced pressure togiveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(trifluoromethoxy)phenyl)acetamide(0.047 g, 0.092 mmol, 67.9% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.97 (s, 1H), 9.69 (t, J=5.83 Hz, 1H), 7.77 (dd, J=1.58,7.88 Hz, 1H), 7.68-7.74 (m, 2H), 7.48-7.56 (m, 3H), 7.43 (d, J=7.88 Hz,1H), 5.11 (dd, J=5.04, 13.24 Hz, 1H), 4.49 (d, J=6.31 Hz, 2H), 4.44 (d,J=17.34 Hz, 1H), 4.28-4.33 (m, 1H), 2.91 (ddd, J=5.36, 13.79, 17.42 Hz,1H), 2.57-2.63 (m, 1H), 2.40 (qd, J=4.26, 13.19 Hz, 1H), 2.00 (dtd,J=2.36, 5.26, 12.65 Hz, 1H). MS (ESI) m/z 512.2 [M+1]⁺.

Example 21 Synthesis of2-(3-bromo-4-(trifluoromethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A.2-(3-bromo-4-(trifluoromethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Mesylicacid (0.050 g, 0.135 mmol) was placed in a vial withN,N-Dimethylformamide (1.0 mL),2-(3-bromo-4-(trifluoromethoxy)phenyl)-2,2-difluoroacetic acid (0.045 g,0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixturewas stirred at room temperature for 18 h. The reaction mixture was takenup in dimethylsulfoxide and purified using reverse-phase semipreparatory HPLC (5-100% acetonitrile+0.1% formic acid in water+0.1%formic acid, over 20 min). Fractions containing desired product werecombined and volatile organics were removed under reduced pressure togive2-(3-bromo-4-(trifluoromethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(0.048 g, 0.081 mmol, 60.1% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.99 (s, 1H), 9.75 (t, J=6.15 Hz, 1H), 8.01 (d, J=1.89 Hz,1H), 7.73-7.78 (m, 2H), 7.69 (d, J=7.57 Hz, 1H), 7.45 (s, 1H), 7.38 (d,J=7.88 Hz, 1H), 5.11 (dd, J=5.04, 13.24 Hz, 1H), 4.41-4.49 (m, 3H),4.28-4.34 (m, 1H), 2.92 (ddd, J=5.36, 13.71, 17.50 Hz, 1H), 2.58-2.64(m, 1H), 2.39 (qd, J=4.41, 13.24 Hz, 1H), 2.01 (dtd, J=2.21, 5.20, 12.61Hz, 1H). MS (ESI) m/z 592.0 [M+2]⁺.

Example 22 Synthesis ofN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoropropanamide

A.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoropropanamide

3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Mesylicacid (0.050 g, 0.135 mmol) was placed in a vial withN,N-Dimethylformamide (1.0 mL), 2,2-difluoropropanoic acid (0.015 g,0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixturewas stirred at room temperature for 18 h. The reaction mixture was takenup in dimethylsulfoxide and purified using reverse-phase semipreparatory HPLC (5-100% acetonitrile+0.1% formic acid in water+0.1%formic acid, over 20 min). Fractions containing desired product werecombined and volatile organics were removed under reduced pressure togiveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoropropanamide(0.016 g, 0.044 mmol, 32.4% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.98 (s, 1H), 9.36 (t, J=5.99 Hz, 1H), 7.71 (d, J=7.88 Hz,1H), 7.49 (s, 1H), 7.42 (d, J=7.88 Hz, 1H), 5.12 (dd, J=5.20, 13.40 Hz,1H), 4.43-4.49 (m, 3H), 4.30-4.35 (m, 1H), 2.92 (ddd, J=5.52, 13.64,17.42 Hz, 1H), 2.58-2.64 (m, 1H), 2.40 (qd, J=4.57, 13.19 Hz, 1H), 2.01(dtd, J=2.21, 5.16, 12.69 Hz, 1H), 1.74-1.84 (m, 3H). MS (ESI) m/z 366.2[M+1]⁺.

Example 23 Synthesis ofN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2,3,3-tetrafluoropropanamide

A.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2,3,3-tetrafluoropropanamide

3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Mesylicacid (0.050 g, 0.135 mmol) was placed in a vial withN,N-Dimethylformamide (1.0 mL), 2,2,3,3-tetrafluoropropanoic acid (0.020g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixturewas stirred at room temperature for 18 h. The reaction mixture was takenup in dimethylsulfoxide and purified using reverse-phase semipreparatory HPLC (5-100% acetonitrile+0.1% formic acid in water+0.1%formic acid, over 20 min). Fractions containing desired product werecombined and volatile organics were removed under reduced pressure togiveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2,3,3-tetrafluoropropanamide(0.013 g, 0.032 mmol, 23.93% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.97 (s, 1H), 9.92 (t, J=5.99 Hz, 1H), 7.71 (d, J=7.88 Hz,1H), 7.47 (s, 1H), 7.41 (d, J=7.88 Hz, 1H), 6.64-6.89 (m, 1H), 5.11 (dd,J=5.04, 13.24 Hz, 1H), 4.50 (d, J=6.31 Hz, 2H), 4.46 (d, J=17.34 Hz,1H), 4.29-4.34 (m, 1H), 2.87-2.95 (m, 1H), 2.57-2.63 (m, 1H), 2.39 (qd,J=4.73, 13.24 Hz, 1H), 2.00 (dtd, J=2.21, 5.24, 12.53 Hz, 1H). MS (ESI)m/z 402.0 [M+1]⁺.

Example 24 Synthesis ofN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluorobutanamide

A.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluorobutanamide

3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Mesylicacid (0.050 g, 0.135 mmol) was placed in a vial withN,N-Dimethylformamide (1.0 mL), 2,2-difluorobutanoic acid (0.017 g,0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixturewas stirred at room temperature for 18 h. The reaction mixture was takenup in dimethylsulfoxide and purified using reverse-phase semipreparatory HPLC (5-100% acetonitrile+0.1% formic acid in water+0.1%formic acid, over 20 min). Fractions containing desired product werecombined and volatile organics were removed under reduced pressure togiveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluorobutanamide(0.027 g, 0.071 mmol, 52.6% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.97 (s, 1H), 9.37 (t, J=5.99 Hz, 1H), 7.70 (d, J=7.88 Hz,1H), 7.47 (s, 1H), 7.41 (d, J=7.88 Hz, 1H), 5.10 (dd, J=5.20, 13.40 Hz,1H), 4.42-4.48 (m, 3H), 4.28-4.34 (m, 1H), 2.91 (ddd, J=5.36, 13.64,17.58 Hz, 1H), 2.57-2.63 (m, 1H), 2.39 (qd, J=4.57, 13.29 Hz, 1H),1.97-2.14 (m, 3H), 0.92 (t, J=7.41 Hz, 3H). MS (ESI) m/z 380.2 [M+1]⁺.

Example 25 Synthesis ofN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-3-hydroxy-3-methylbutanamide

A.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-3-hydroxy-3-methylbutanamide

3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Mesylicacid (0.050 g, 0.135 mmol) was placed in a vial withN,N-Dimethylformamide (1.0 mL), 2,2-difluoro-3-hydroxy-3-methylbutanoicacid (0.021 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406mmol), and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixturewas stirred at room temperature for 18 h. The reaction mixture was takenup in dimethylsulfoxide and purified using reverse-phase semipreparatory HPLC (5-100% acetonitrile+0.1% formic acid in water+0.1%formic acid, over 20 min). Fractions containing desired product werecombined and volatile organics were removed under reduced pressure togiveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-3-hydroxy-3-methylbutanamide(0.049 g, 0.120 mmol, 88% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.97 (s, 1H), 9.07 (t, J=5.99 Hz, 1H), 7.68 (d, J=8.20 Hz,1H), 7.50 (s, 1H), 7.43 (d, J=7.25 Hz, 1H), 5.46 (br. s., 1H), 5.10 (dd,J=5.04, 13.24 Hz, 1H), 4.41-4.46 (m, 3H), 4.27-4.33 (m, 1H), 2.86-2.96(m, 1H), 2.57-2.63 (m, 1H), 2.39 (qd, J=4.57, 13.19 Hz, 1H), 2.00 (dtd,J=2.36, 5.26, 12.65 Hz, 1H), 1.24 (s, 6H). MS (ESI) m/z 410.2 [M+1]⁺.

Example 262-(3-chloro-4-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. 1-(3-chloro-4-methylphenyl)ethanone

To a stirred solution of 3-chloro-4-methylbenzonitrile (3 g, 19.86 mmol)in benzene (25 mL) was added methyl magnesium iodide (6.6 mL, 19.86mmol, 3M in diethyl ether) at room temperature and stirred at 80° C. for8 h. Then the reaction mixture was cooled to room temperature and added6N hydrochloric acid (25 mL) and stirred at 80° C. for 6 h. The reactionmixture was cooled to room temperature and extracted with ethyl acetate(3×50 mL). The combined organic layers were washed with water (2×20 mL),brine (20 mL), dried over sodium sulphate and concentrated to afford1-(3-chloro-4-methylphenyl)ethanone (2 g, 11.90 mmol, 60% yield) asoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (d, J=1.8 Hz, 1H),7.82 (dd, J=7.8, 1.8 Hz, 1H), 7.51 (dd, J=7.7, 1.0 Hz, 1H), 2.57 (s,3H), 2.40 (s, 3H).

B. Ethyl 2-(3-chloro-4-methylphenyl)-2-oxoacetate

To a stirred solution of 1-(3-chloro-4-methylphenyl) ethanone (500 mg,2.97 mmol) in pyridine (5 mL) was added selenium dioxide (660 mg, 5.95mmol) and stirred for 12 h at 100° C. The reaction mixture was dilutedwith dichloromethane (20 mL) and filtered through Celite pad. To thefiltrate was added ethyl chloroformate (2 mL) at 0° C. and stirred atroom temperature for 2 h. The reaction mixture was acidified with 1Naqueous hydrochloric acid (up to pH-4) and extracted with ethyl acetate(3×10 mL). The combined organic layers were washed with water (2×5 mL),brine (5 mL), dried over sodium sulphate and concentrated to affordethyl 2-(3-chloro-4-methylphenyl)-2-oxoacetate (300 mg, 1.32 mmol, 45%)as a brown liquid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.99 (dd, J=5.5, 1.7 Hz,1H), 7.86 (dd, J=7.9, 1.8 Hz, 1H), 7.59 (dd, J=11.6, 7.9 Hz, 1H), 4.42(q, J=7.1 Hz, 2H), 2.44 (s, 3H), 1.33 (t, J=7.1 Hz, 3H).

C. Ethyl 2-(3-chloro-4-methylphenyl)-2,2-difluoroacetate

To ethyl 2-(3-chloro-4-methylphenyl)-2-oxoacetate (300 mg, 1.32 mmol)was added diethyl amino sulfur trifluoride (2 mL) and stirred for 12 hat room temperature. The reaction mixture was neutralized with aqueoussaturated sodium bicarbonate (up to pH-8) and extracted with ethylacetate (3×10 mL). The combined organic layers were washed with water(2×5 mL), brine (10 mL), dried over sodium sulphate and was concentratedto afford ethyl 2-(3-chloro-4-methylphenyl)-2,2-difluoroacetate (200 mg,0.804 mmol, 61%) as a brown liquid. ¹H NMR (400 MHz, DMSO-d₆) δ7.63-7.52 (m, 2H), 7.47 (dd, J=7.9, 1.9 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H),2.39 (s, 3H), 1.23 (t, J=7.1 Hz, 4H).

D. 2-(3-chloro-4-methylphenyl)-2,2-difluoroacetic acid

To a cold (0° C.) stirred solution of ethyl2-(3-chloro-4-methylphenyl)-2,2-difluoroacetate (200 mg, 0.806 mmol) inmethanol/tetrahydrofuran/water (10 mL, 1:1:1) was added lithiumhydroxide monohydrate (169 mg, 4.03 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous hydrochloric acid (10 mL) andextracted with ethyl acetate (2×15 mL). The combined organic layers werewashed with brine (20 mL), dried over sodium sulphate and concentratedto afford 2-(3-chloro-4-methylphenyl)-2,2-difluoroacetic acid (150 mg,0.68 mmol, 84% yield) as a brown semi solid. ¹H NMR (300 MHz, DMSO-d₆) δ7.61-7.50 (m, 2H), 7.45 (dd, J=8.0, 1.8 Hz, 1H), 2.39 (s, 3H).

E.2-(3-Chloro-4-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a cold (0° C.) stirred solution of 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methane sulfonate (200mg, 0.619 mmol) in N,N-dimethylformamide (20 mL) was added2-(3-chloro-4-methylphenyl)-2,2-difluoroacetic acid (150 mg, 0.68 mmol)followed by N,N-diisopropylethylamine (240 mg, 1.85 mmol),1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (352 mg, 0.92 mmol) and stirred at roomtemperature for 12 h. The reaction mixture was diluted with water (100mL) and extracted with ethyl acetate (2×10 mL) and the combined organiclayers were washed with brine (20 mL), dried over sodium sulphate andconcentrated under vacuum. The product was purified by Reveleris C-18reversed phase column using 70% acetonitrile in aqueous formic acid(0.1%) to give2-(3-chloro-4-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(40 mg, 0.08 mmol, 14% yield) as an off white solid. MS (ESI) m/z 476.18[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.66 (t, J=6.0 Hz,1H), 7.68 (d, J=7.9 Hz, 1H), 7.61-7.50 (m, 2H), 7.49-7.33 (m, 3H), 5.10(dd, J=13.3, 5.0 Hz, 1H), 4.51-4.12 (m, 4H), 2.98-2.83 (m, 1H),2.65-2.55 (m, 1H), 2.46-2.27 (m, 4H), 2.06-1.93 (m, 1H).

Example 27N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(trifluoromethylthio)phenyl)acetamide

A. 1-(4-(Trifluoromethylthio)phenyl)ethanone

In a stirred and evacuated round bottom flask were taken potassiumphosphate (19.38 g, 91.44 mmol), molecular sieves (5 g, 4 Å), sulphur-8(2.92 g, 91.44 mmol), silver carbonate (16.80 g, 60.96 mmol),(4-acetylphenyl)boronic acid (5 g, 30.48 mmol), copper (1) thiocyanate(370 mg, 3.04 mmol) and 1,10-phenanthroline (1.09 g, 6.09). Trimethyl(trifluoromethyl)silane (21.67 g, 152.43 mmol) in dryN,N-dimethylformamide (50 mL) was added to the round bottom flask andstirred for 12 h at room temperature. The reaction mixture was filteredthrough Celite pad, cold water (20 mL) was added and extracted withethyl acetate (3×50 mL). The combined organic layers were washed withwater (2×10 mL), brine (10 mL), dried over sodium sulphate andconcentrated. The resultant residue was purified by columnchromatography (100-200 silica) using 10% ethyl acetate in pet.ether toafford 1-(4-(trifluoromethylthio)phenyl)ethanone (2.8 g, 13.20 mmol,45%) as a light yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ 8.03-7.89 (m,2H), 7.75 (d, J=7.9 Hz, 2H), 2.80-2.42 (m, 3H).

B. Ethyl 2-oxo-2-(4-(trifluoromethylthio)phenyl)acetate

To a stirred solution of 1-(4-(trifluoromethylthio)phenyl)ethanone (2.5g, 11.79 mmol) in pyridine (50 mL) was added selenium dioxide (2.61 g,23.58 mmol) and stirred for 4 h at 100° C. The reaction mixture wasdiluted with dichloromethane (50 mL) and filtered through Celite pad. Tothe filtrate was added dichloromethane (30 mL) followed by ethylchloroformate (5 mL) at 0° C. and stirred for 2 h. The pH of thereaction mixture was adjusted to pH-4 with 1N aqueous hydrochloric acidand extracted with ethyl acetate (3×50 mL). The combined organic layerswere washed with water (2×10 mL), brine (10 mL), dried over sodiumsulphate and concentrated. The resultant residue was purified by columnchromatography (100-200 silica) using 10% ethyl acetate in pet.ether toafford ethyl 2-oxo-2-(4-(trifluoromethylthio)phenyl)acetate (2.0 g, 7.19mmol, 62%) as a liquid. ¹H NMR (400 MHz, CDCl₃) δ 8.12-8.04 (m, 2H),7.84-7.72 (m, 2H), 4.61-4.33 (m, 2H), 1.49-1.34 (m, 3H).

C. Ethyl 2,2-difluoro-2-(4-(trifluoromethylthio)phenyl)acetate

To ethyl 2-oxo-2-(4-(trifluoromethylthio)phenyl)acetate (2.0 g, 7.19mmol) was added diethyl amino sulfur trifluoride (1.4 mL, 10.79 mmol)and stirred for 12 h at room temperature. The reaction mixture wasneutralized with aqueous saturated sodium bicarbonate (up to pH-8) andextracted with ethyl acetate (3×50 mL). The combined organic layer waswashed with water (2×10 mL), brine (10 mL), dried over sodium sulphateand concentrated to afford ethyl2,2-difluoro-2-(4-(trifluoromethylthio)phenyl)acetate (2.0 g, 6.66 mmol,95%) as a liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J=8.2 Hz, 2H), 4.32(q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).

D. 2,2-Difluoro-2-(4-(trifluoromethylthio)phenyl)acetic acid

To a stirred cold (0° C.) solution of ethyl2,2-difluoro-2-(4-(trifluoromethylthio)phenyl)acetate (1.5 g, 5.0 mmol)in aqueous methanol (10 mL, 80%) was added sodium hydroxide (0.4 g, 10.0mmol) and stirred at room temperature for 6 h. The reaction mixture wasconcentrated and the residue was neutralized with 10% aqueoushydrochloric acid (10 mL) and extracted with ethyl acetate (2×20 mL).The combined organic layers were washed with brine (20 mL), dried oversodium sulphate and concentrated to afford2,2-difluoro-2-(4-(trifluoromethylthio)phenyl)acetic acid (1 g, 3.67mmol, 73% yield) as an brown solid. MS (ESI) m/z 271.22 [M−1]⁺.

E.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(trifluoromethylthio)phenyl)acetamide

To a cold (0° C.) stirred solution of 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methane sulfonate (500mg, 1.61 mmol) in N,N-dimethylformamide (20 mL) was added2,2-difluoro-2-(4-(trifluoromethylthio)phenyl)acetic acid (520 mg, 1.94mmol), N,N-diisopropylethylamine (0.86 mL, 4.8 mmol) followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (920 mg, 2.4 mmol) and stirred at roomtemperature for 12 h. The reaction mixture was diluted with water (100mL) and the solid precipitated was filtered, dried under vacuum andpurified by Reveleris C-18 reversed phase column using 70% acetonitrilein aqueous formic acid (0.1%) to giveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(trifluoromethylthio)phenyl)acetamide (60 mg, 0.11 mmol, 7% yield) as an off white solid. MS(ESI) m/z 528.07 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.76(t, J=6.1 Hz, 1H), 7.91 (d, J=8.1 Hz, 2H), 7.81-7.61 (m, 3H), 7.53-7.21(m, 2H), 5.10 (dd, J=13.4, 5.1 Hz, 1H), 4.57-4.10 (m, 4H), 2.85-2.93 (m,1H), 2.72-2.56 (m, 1H), 2.42-2.26 (m, 1H), 2.10-1.94 (m, 1H).

Example 282-(3-Chloro-4-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. Ethyl 2-(3-chloro-4-methoxyphenyl)-2-oxoacetate

To a stirred solution of 1-(3-chloro-4-methoxyphenyl)ethanone (2 g,10.83 mmol) in pyridine (15 mL) was added selenium dioxide (3 g, 27.08mmol) at room temperature. The reaction mixture was stirred at 100° C.for 16 h. The reaction mixture was filtered through a Celite pad andwashed with dichloromethane (30 mL). Ethyl chloroformate (6 mL) wasadded to the filtrate at 0° C. and stirred at room temperature for 4 h.The reaction mixture was quenched with ice water and extracted withdichloromethane (3×25 mL). The combined organic layers were washed with1N hydrochloride solution (20 mL) and brine (20 mL), dried over sodiumsulfate, filtered and concentrated to afford ethyl2-(3-chloro-4-methoxyphenyl)-2-oxoacetate (1.45 g, 5.98 mmol, 55% yield)as a colourless liquid. MS (ESI) m/z 242.1 [M]⁺

B. Ethyl 2-(3-chloro-4-methoxyphenyl)-2,2-difluoroacetate

Ethyl 2-(3-chloro-4-methoxyphenyl)-2-oxoacetate (1.45 g, 5.99 mmol) wasadded in portion into diethylaminosulfur trifluoride (2.35 mL) at 0° C.and stirred at room temperature for 16 h. The reaction mixture wasquenched with aqueous sodium bicarbonate solution and extracted withethyl acetate (3×20 mL). The combined organic layers were washed withbrine (20 mL), dried over sodium sulphate, filtered and concentrated.Obtained crude was purified by flash column chromatography (100-200silica gel, 10% ethyl acetate in pet ether) to afford ethyl2-(3-chloro-4-methoxyphenyl)-2,2-difluoroacetate (1 g, 3.78 mmol, 63%yield) as a colourless liquid. MS (ESI) m/z 264.1 [M]⁺.

C. 2-(3-Chloro-4-methoxyphenyl)-2,2-difluoroacetic acid

To a stirred solution of ethyl2-(3-chloro-4-methoxyphenyl)-2,2-difluoroacetate (1 g, 3.78 mmol) intetrahydrofuran: ethanol: water (15 mL, 1:1:1) was added lithiumhydroxide monohydrate (480 mg, 11.36 mmol) and stirred at roomtemperature for 16 h. The reaction mixture was concentrated underreduced pressure and the resultant residue was dissolved in water (20mL) and washed with ethyl acetate (2×15 mL). Aqueous layer was acidifiedwith 1N hydrochloride solution and extracted with ethyl acetate (3×15mL). The combined organic layer was washed with brine (15 mL), driedover sodium sulphate, filtered and concentrated to afford2-(3-chloro-4-methoxyphenyl)-2,2-difluoroacetic acid (550 mg, 2.32 mmol,61% yield) as semi-solid compound. ¹H NMR (300 MHz, DMSO-d₆) δ 7.57-7.52(m, 2H), 7.29 (d, J=8.7 Hz, 1H), 3.92 (s, 3H).

D.2-(3-Chloro-4-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a stirred solution of3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) in dry N,N-dimethylformamide (6 mL)was added 2-(3-chloro-4-methoxyphenyl)-2,2-difluoroacetic acid (252 mg,1.07 mmol) followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (442 mg, 1.16 mmol) and diisoproylethylamine(375 mg, 2.91 mmol) at 0° C. and stirred at room temperature for 16 h.The reaction mixture was concentrated under reduced pressure andobtained residue was dissolved in water (15 mL) and extracted with ethylacetate (3×15 mL). The combined organic layer was washed with brine (10mL), dried over sodium sulfate, filtered and concentrated. The resultantresidue was purified by Reveleris C-18 reversed phase Grace columnchromatography (45-55% acetonitrile in aqueous 0.1% formic acid) toafford2-(3-Chloro-4-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide (58 mg, 11.7 mmol, 12% yield) as an off-white solid. MS (ESI)m/z 492.47 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.62 (t,1H), 7.68 (d, J=7.8 Hz, 1H), 7.60 (d, J=2.3 Hz, 1H), 7.53 (d, J=8.7 Hz,1H), 7.41 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.7 Hz, 1H), 5.10(dd, J=13.2, 5.1 Hz, 1H), 4.45 (d, J=5.4 Hz, 2H), 4.42 (d, J=17.9 Hz,1H), 4.28 (d, J=17.9 Hz, 1H), 3.91 (s, 3H), 2.96-2.86 (m, 1H), 2.64-2.55(m, 1H), 2.47-2.25 (m, 1H), 2.08-1.94 (m, 1H).

Example 29N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(m-tolyl)acetamide

A. Ethyl 2-oxo-2-m-tolylacetate

To a stirred solution of 1-m-tolylethanone (3.0 g, 22.37 mmol) inpyridine (50 mL) was added selenium dioxide (4.96 g, 44.74 mmol) andstirred for 16 h at 100° C. The reaction mixture was diluted withdichloromethane (50 mL) and filtered through Celite pad. To the filtratewas added ethyl chloroformate (6 mL) at 0° C. and stirred for 2 h. Thereaction mixture was neutralized with 1N aqueous hydrochloric acid (upto pH-4) and extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with water (2×100 mL), brine (100 mL) anddried over sodium sulphate and concentrated. The resultant residue waspurified by column chromatography (100-200 silica) using 10% ethylacetate in pet.ether to afford ethyl 2-oxo-2-m-tolylacetate (2.0 g,10.41 mmol, 46.6%) as a liquid. GC-MS (ESI) m/z 192.2.

B. Ethyl 2,2-difluoro-2-m-tolylacetate

To a stirred solution of ethyl 2-oxo-2-m-tolylacetate (2.0 g, 10.41mmol) was reacted with diethyl amino sulfur trifluoride (3.41 mL, 26.02mmol) and stirred for 12 h at room temperature. The reaction mixture wasneutralized with aqueous saturated sodium bicarbonate (up to pH-8) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×50 mL), brine (50 mL), dried over sodium sulphateand concentrated to afford ethyl 2,2-difluoro-2-m-tolylacetate (1.2 g,5.60 mmol, 52.4%) as a liquid. GC-MS (ESI) m/z 214.1.

C. 2,2-Difluoro-2-m-tolylacetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-m-tolylacetate (1.2 g, 7.47 mmol) intetrahydrofuran-methanol-water solvent mixture (45 mL, 1:1:1), was addedlithium hydroxide (1.85 g, 44.84 mmol) and stirred at room temperaturefor 2 h. The reaction mixture was concentrated and the residue wasneutralized with 10% aqueous hydrochloric acid (10 mL) and extractedwith ethyl acetate (2×20 mL). The combined organic layers were washedwith brine (20 mL), dried over sodium sulphate and concentrated toafford 2, 2-difluoro-2-m-tolylacetic acid (900 mg, 4.83 mmol, 86.5%yield) as a brown solid. MS (ESI) m/z 185.21 [M−1]⁻.

D.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(m-tolyl)acetamide

To a cold (0° C.) stirred solution of 2,2-difluoro-2-m-tolylacetic acid(216.6 mg, 0.970 mmol) in pyridine (10 mL) was added phosphorustrichloride (0.3 mL, 2.912 mmol) and stirred at 0° C.-5° C. for 1 h.(300 mg, 2.40 mmol) was added to the reaction mixture at 0° C. andcontinued stirring at room temperature for 1 h. The reaction mixture wasneutralized with aqueous saturated sodium bicarbonate (up to pH-8) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×50 mL), brine (50 mL), dried over sodium sulphateand concentrated. The crude product was purified by Reveleris C-18reversed phase Grace column chromatography using 45% acetonitrile inaqueous formic acid (0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(m-tolyl)acetamide (63 mg, 0.147 mmol, 14.7%yield) as an off white solid. MS (ESI) m/z 442.25 [M+1]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.61 (t, J=6.1 Hz, 1H), 7.68 (d, J=7.8Hz, 1H), 7.48-7.32 (m, 6H), 5.10 (dd, J=13.3, 5.0 Hz, 1H), 4.49-4.22 (m,4H), 2.98-2.82 (m, 1H), 2.64-2.53 (m, 1H), 2.45-2.24 (m, 4H), 2.05-1.93(m, 1H).

Example 30N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxyphenyl)acetamide

A. 1-(4-Isopropoxyphenyl)ethanone

To a stirred solution of 1-(4-hydroxyphenyl)ethanone (2.5 g, 18.38 mmol)in N,N-dimethylformamide was added potassium carbonate (6.34 g, 45.95mmol) followed by isopropyl iodide (4.59 g, 27.57 mmol) at 0° C. andthen heated at 100° C. for 16 h. The reaction mixture was quenched withice water and extracted with ethyl acetate (3×25 mL). The combinedorganic layers were washed with brine (25 mL), dried over sodiumsulphate, filtered, concentrated. Obtained crude compound was purifiedby flash column chromatography (100-200 silica gel, 20% ethylacetate/pet ether) to afford 1-(4-isopropoxyphenyl)ethanone (2 g, 11.23mmol, 61% yield) as a liquid. MS (ESI) m/z 179.13 [M+H]⁺.

B. Ethyl 2-(4-isopropoxyphenyl)-2-oxoacetate

To a stirred solution of 1-(4-isopropoxyphenyl)ethanone (3 g, 16.85mmol) in pyridine (15 mL) was added selenium dioxide (4.67 g, 42.1 mmol)at room temperature and stirred at 100° C. for 16 h. The reactionmixture was filtered through a Celite pad and washed withdichloromethane (30 mL). Filtrate was cooled to 0° C., treated withethyl chloroformate (6 mL) and stirred at room temperature for 4 h. Thereaction mixture was quenched with ice water and extracted withdichloromethane (3×30 mL). The combined organic layers were washed with1N hydrochloride solution (30 mL), brine (30 mL), dried over sodiumsulphate, filtered and concentrated to afford ethyl2-(4-isopropoxyphenyl)-2-oxoacetate (3 g, 12.76 mmol, 75% yield) as acolourless liquid. MS (ESI) m/z 236.2 [M]⁺.

C. Ethyl 2,2-difluoro-2-(4-isopropoxyphenyl)acetate

To ethyl 2-(4-isopropoxyphenyl)-2-oxoacetate (3 g, 12.76 mmol) was addeddiethylaminosulfur trifluoride (4.9 mL) at 0° C. and stirred at roomtemperature for 16 h. The reaction mixture was quenched with aqueoussodium bicarbonate solution and extracted with ethyl acetate (3×30 mL).The combined organic layer was washed with brine (30 mL), dried oversodium sulphate, filtered and concentrated. Obtained crude was purifiedby flash column chromatography (100-200 silica gel, 10% ethylacetate/pet ether) to afford ethyl2,2-difluoro-2-(4-isopropoxyphenyl)acetate (2 g, 7.75 mmol, 61% yield)as a colourless liquid. MS (ESI) m/z 258.2 [M+H]⁺.

D. 2,2-Difluoro-2-(4-isopropoxyphenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(4-isopropoxyphenyl)acetate (2 g, 7.75 mmol) intetrahydrofuran:ethanol:water (20 mL, 1:1:1) was added lithium hydroxidemonohydrate (1.6 g, 38.75 mmol) and stirred at room temperature for 16h. The reaction mixture was concentrated under reduced pressure and theresultant residue was dissolved in water (20 mL) and washed with ethylacetate (2×20 mL). Aqueous layer was acidified with 1N hydrochloridesolution and extracted with ethyl acetate (3×20 mL). The combinedorganic layer was washed with brine (20 mL), dried over sodium sulphate,filtered and concentrated to afford2,2-difluoro-2-(4-isopropoxyphenyl)acetic acid (1.2 g, 5.21 mmol, 67%yield) as semi-solid compound. ¹H NMR (300 MHz, DMSO-d₆) δ 7.47 (d,J=8.7 Hz, 2H), 7.03 (d, J=9 Hz, 2H), 4.71-4.63 (m, 1H), 1.28 (d, J=6 Hz,6H).

E.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxyphenyl)acetamide

To an ice cold solution of 2,2-difluoro-2-(4-isopropoxyphenyl)aceticacid (267 mg, 1.16 mmol) in pyridine (6 mL) was added phosphorylchloride (0.27 mL, 2.91 mmol) dropwise and stirred at 0-5° C. for 1 h.Then, 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) was added into the reaction mixtureand stirred at room temperature for 30 min. The reaction mixture wasneutralized with aqueous saturated sodium bicarbonate (up to pH-8) andextracted with ethyl acetate (3×15 mL). The combined organic layer waswashed with water (15 mL), brine (15 mL), dried over sodium sulphate,filtered and concentrated. The resultant residue was purified byReveleris C-18 reversed phase column chromatography (45-55% acetonitrilein aqueous formic acid 0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxyphenyl)acetamide (27 mg, 0.05 mmol, 6% yield) as an off-white solid. MS (ESI)m/z 486.09 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.56 (t,J=6.3 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.43-7.33(m, 2H), 7.03 (d, J=8.4 Hz, 2H), 5.10 (dd, J=13.3, 5.2 Hz, 1H),4.74-4.62 (m, 1H), 4.49-4.27 (m, 4H), 3.02-2.83 (m, 1H), 2.69-2.58 (m,1H), 2.39-2.28 (m, 1H), 2.05-1.95 (m, 1H), 1.27 (d, J=6.0 Hz, 6H).

Example 312-(3,4-Difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. Ethyl 2-(3,4-difluorophenyl)-2-oxoacetate

To a stirred solution of 1-(3,4-difluorophenyl)ethanone (1 g, 6.4 mmol)in pyridine (15 mL) was added selenium dioxide (1.7 g, 16.01 mmol) atroom temperature. The reaction mixture was stirred at 100° C. for 16 h.The reaction mixture was filtered through Celite pad and washed withdichloromethane (30 mL). ethyl chloroformate (4 mL) was added to thefiltrate at 0° C. and stirred at room temperature for 4 h. The reactionmixture was quenched with ice water and extracted with dichloromethane(3×25 mL). The combined organic layers were washed with 1N hydrochloridesolution (20 mL), brine (20 mL), dried over sodium sulfate, filtered andconcentrated to afford ethyl 2-(3,4-difluorophenyl)-2-oxoacetate (750mg, 3.50 mmol, 55% yield) as a colourless liquid. MS (ESI) m/z 214.1[M]⁺.

B. Ethyl 2-(3,4-difluorophenyl)-2,2-difluoroacetate

Ethyl 2-(3,4-difluorophenyl)-2-oxoacetate (750 mg, 3.5 mmol) was addedto diethylamino sulfur trifluoride (1.37 mL) under nitrogen atmosphereat 0° C. and stirred at room temperature for 16 h. The reaction mixturewas quenched with aqueous sodium bicarbonate solution and extracted withethyl acetate (3×20 mL). The combined organic layer was washed withbrine (20 mL), dried over sodium sulfate, filtered and concentrated.Obtained crude was purified by flash column chromatography (100-200silica gel, 10% ethyl acetate in pet ether) to afford ethyl2-(3,4-difluorophenyl)-2,2-difluoroacetate (520 mg, 2.20 mmol, 63%yield) as a colourless liquid. MS (ESI) m/z 236.1 [M]⁺.

C. 2-(3,4-Difluorophenyl)-2,2-difluoroacetic acid

To a stirred solution of ethyl2-(3,4-difluorophenyl)-2,2-difluoroacetate (500 mg, 2.11 mmol) intetrahydrofuran:ethanol:water (15 mL, 1:1:1) was added lithium hydroxidemonohydrate (267 mg, 6.35 mmol) and stirred at room temperature for 16h. The volatiles were removed under reduced pressure and obtained crudewas dissolved in water (15 mL) and washed with ethyl acetate (2×10 mL).Aqueous layer was acidified with 1N hydrochloride solution and extractedwith ethyl acetate (3×15 mL). The combined organic layer was washed withbrine (10 mL) dried over sodium sulfate, filtered and concentrated toafford 2-(3,4-difluorophenyl)-2,2-difluoroacetic acid (300 mg, 1.44mmol, 68% yield) as semi-solid compound. MS (ESI) m/z 208.1 [M]⁺.

D.2-(3,4-Difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a stirred solution of3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) in dry N,N-dimethylformamide (6 mL)was added 2-(3,4-difluorophenyl)-2,2-difluoroacetic acid (222 mg, 1.07mmol) followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (442 mg, 1.16 mmol) and diisoproylethylamine(0.5 mL, 2.91 mmol) at 0° C. and stirred at room temperature for 16 h.The reaction mixture was concentrated under reduced pressure and theobtained crude was dissolved in water (10 mL) and extracted with ethylacetate (3×10 mL). The combined organic layers were washed with brine(10 mL), dried over sodium sulfate, filtered and concentrated. The crudecompound was purified by Reveleris C-18 reversed phase Grace columnchromatography (45-55% acetonitrile in 0.1% aqueous formic acid toafford2-(3,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide (75 mg, 0.16 mmol, 17% yield) as an off-white solid. MS (ESI)m/z 463.99 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.69 (t,J=5.9 Hz, 1H), 7.72-7.62 (m, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.51-7.44 (m,1H), 7.43 (s, 1H), 7.37 (d, J=7.8 Hz, 1H), 5.10 (dd, J=13.3, 5.0 Hz,1H), 4.46 (d, J=5.4 Hz, 2H), 4.43 (d, J=17.4 Hz, 1H), 4.29 (d, J=17.1Hz, 1H), 2.98-2.87 (m, 1H), 2.65-2.56 (m, 1H), 2.45-2.29 (m, 1H),2.08-1.90 (m, 1H).

Example 32N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-fluorophenyl)acetamide

A. Ethyl 2-(3-fluorophenyl)-2-oxoacetate

To a stirred solution of 1-(3-fluorophenyl)ethanone (2 g, 14.48 mmol) inpyridine (15 mL) was added selenium dioxide (4.01 g, 36.19 mmol) at roomtemperature. The reaction mixture was stirred at 100° C. for 16 h. Thereaction mixture was filtered through Celite pad and washed withdichloromethane (30 mL). Ethyl chloroformate (6 mL) was added to thefiltrate at 0° C. and stirred at room temperature for 4 h. The reactionmixture was quenched with ice water and extracted with dichloromethane(3×25 mL). The combined organic layers were washed with 1N hydrochloridesolution (20 mL), brine (20 mL), dried over sodium sulfate, filtered andconcentrated to afford ethyl 2-(3-fluorophenyl)-2-oxoacetate (1.5 g,7.65 mmol, 53% yield) as a colourless liquid. MS (ESI) m/z 196.1 [M]⁺.

B. Ethyl 2,2-difluoro-2-(3-fluorophenyl)acetate

Ethyl 2-(3-fluorophenyl)-2-oxoacetate (1.5 g, 7.65 mmol) was added todiethylaminosulfur trifluoride (3 mL) at 0° C. and stirred at roomtemperature for 16 h. The reaction mixture was quenched with aqueoussodium bicarbonate solution and extracted with ethyl acetate (3×20 mL).The combined organic layers were washed with brine (20 mL), dried oversodium sulfate, filtered and concentrated. Obtained crude was purifiedby flash column chromatography (100-200 silica gel, 10% ethyl acetate inpet ether) to afford ethyl 2,2-difluoro-2-(3-fluorophenyl)acetate (850mg, 3.89 mmol, 90% yield) as a colourless liquid. MS (ESI) m/z 218.1[M]⁺.

C. 2,2-Difluoro-2-(3-fluorophenyl)acetic acid

To a stirred solution of ethyl 2,2-difluoro-2-(3-fluorophenyl)acetate(850 mg, 3.89 mmol) in tetrahydrofuran:ethanol:water (15 mL, 1:1:1) wasadded lithium hydroxide monohydrate (491 mg, 11.69 mmol) and stirred atroom temperature for 16 h. The reaction mixture was concentrated underreduced pressure and obtained crude was dissolved in water (15 mL) andwashed with ethyl acetate (2×10 mL). The aqueous layer was acidifiedwith 1N hydrochloride solution and extracted with ethyl acetate (3×15mL). The combined organic layers were washed with brine (10 mL) driedover sodium sulfate, filtered and concentrated to afford2,2-difluoro-2-(3-fluorophenyl)acetic acid (500 mg, 2.63 mmol, 67%yield) as semi-solid compound. MS (ESI) m/z 190.1 [M]⁺.

D.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-fluorophenyl)acetamide

To a stirred solution of3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (203 mg, 1.07 mmol) in dry N,N-dimethylformamide. (6 mL)was added 2,2-difluoro-2-(3-fluorophenyl)acetic acid (300 mg, 0.97 mmol)followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (442 mg, 1.16 mmol) andN,N-diisopropylethylamine (375 mg, 2.91 mmol) at 0° C. and stirred atroom temperature for 16 h. The reaction mixture was concentrated underreduced pressure and obtained crude was dissolved in water (10 mL) andextracted with ethyl acetate (3×10 mL). The combined organic layers werewashed with brine (10 mL), dried over sodium sulphate, filtered andconcentrated. Obtained crude compound was purified by Reveleris C-18reversed phase column chromatography (45-55% acetonitrile in 0.1%aqueous formic acid to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-fluorophenyl)acetamide(45 mg, 0.1 mmol, 10% yield) as an off-white solid. MS (ESI) m/z 446.04[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.68 (t, J=5.9 Hz,1H), 7.67 (d, J=8.1 Hz, 1H), 7.60 (dd, J=13.5, 7.8 Hz, 1H), 7.47-7.41(m, 4H), 7.36 (d, J=8.1 Hz, 1H), 5.10 (dd, J=13.3, 5.0 Hz, 1H), 4.46 (d,J=5.7 Hz, 2H), 4.42 (d, J=15.0 Hz, 1H), 4.28 (d, J=17.4 Hz, 1H),2.96-2.86 (m, 1H), 2.65-2.54 (m, 1H), 2.46-2.28 (m, 1H), 2.05-1.92 (m,1H).

Example 33N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(trifluoromethyl)pyridin-2-yl)acetamide

A.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(trifluoromethyl)pyridin-2-yl)acetamide

3-(5-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, mesylicacid (0.050 g, 0.135 mmol) was placed in a vial withN,N-dimethylformamide (1.0 mL),2,2-difluoro-2-(3-(trifluoromethyl)pyridin-2-yl)acetic acid (0.033 g,0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixturewas stirred at RT for 18 h. The reaction mixture was taken up indimethylsulfoxide and purified using reverse-phase semi preparatory HPLC(5-100% acetonitrile+0.1% formic acid in water+0.1% formic acid, over 20min). Fractions containing desired product were combined and volatileorganics were removed under reduced pressure to giveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(trifluoromethyl)pyridin-2-yl)acetamide(0.033 g, 0.066 mmol, 49.1% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.98 (s, 1H), 9.59 (t, J=6.15 Hz, 1H), 8.99 (d, J=4.73 Hz,1H), 8.47 (dd, J=1.26, 8.20 Hz, 1H), 7.88 (dd, J=4.73, 8.20 Hz, 1H),7.74 (d, J=7.57 Hz, 1H), 7.60 (s, 1H), 7.51 (dd, J=0.63, 7.88 Hz, 1H),5.12 (dd, J=5.20, 13.40 Hz, 1H), 4.55 (d, J=6.31 Hz, 2H), 4.49 (d,J=17.34 Hz, 1H), 4.32-4.37 (m, 1H), 2.88-2.97 (m, 1H), 2.58-2.64 (m,1H), 2.36-2.46 (m, 1H), 2.02 (dtd, J=2.21, 5.16, 12.69 Hz, 1H). MS (ESI)m/z 497.4 [M+1]⁺.

Example 34N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropylphenyl)acetamide

A. Ethyl 2-(4-isopropylphenyl)-2-oxoacetate

To a stirred solution of 1-(4-isopropylphenyl)ethanone (2.0 g, 12.33mmol) in pyridine (25 mL) was added selenium dioxide (3.42 g, 30.82mmol) and stirred for 16 h at 100° C. The reaction mixture was dilutedwith dichloromethane (50 mL) and filtered through Celite pad. To thefiltrate was added ethyl chloroformate (6 mL) at 0° C. and stirred for 2h. The reaction mixture was diluted with water (50 mL) and extractedwith dichloromethane (3×100 mL). The combined organic layers were washedwith water (2×50 mL), brine (50 mL), dried over sodium sulphate andconcentrated to afford ethyl 2-(4-isopropylphenyl)-2-oxoacetate (2.0 g,9.09 mmol, 74% yield). MS (ESI) m/z 221.29 [M+1]⁺.

B. Ethyl 2,2-difluoro-2-(4-isopropylphenyl)acetate

To ethyl 2-(4-isopropylphenyl)-2-oxoacetate (1.0 g, 4.27 mmol) was addeddiethyl amino sulfur trifluoride (3 mL) at 0° C. and stirred at roomtemperature for 16 h. The reaction mixture was neutralized with aqueoussaturated sodium bicarbonate (up to pH-8) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with water(2×25 mL), brine (25 mL), dried over sodium sulphate and concentrated toafford ethyl 2,2-difluoro-2-(4-isopropylphenyl)acetate (1.0 g, 4.13mmol, 91% yield). GCMS (m/z) 242.2 [M]⁺.

C. 2,2-Difluoro-2-(4-isopropylphenyl)acetic acid

To a stirred solution of ethyl 2,2-difluoro-2-(4-isopropylphenyl)acetate(1.0 g, 4.13 mmol) in tetrahydrofuran:methanol:water (30 mL, 1:1:1) wasadded lithium hydroxide (868 mg, 20.66 mmol) and stirred at roomtemperature for 4 h. The reaction mixture was concentrated and theresidue was neutralized with saturated potassium bisulphate (20 mL) andextracted with ethyl acetate (2×25 mL). The combined organic layers werewashed with brine (25 mL), dried over sodium sulphate and concentratedto afford 2,2-difluoro-2-(4-isopropylphenyl)acetic acid (700 mg, 3.27mmol, 79% yield) as an brown liquid. MS (ESI) m/z 213.33 [M−1]⁺.

D.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropylphenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(4-isopropylphenyl)acetic acid (200 mg, 0.93 mmol) inpyridine (20 mL) was added phosphoryl chloride (429 mg, 2.80 mmol)dropwise and stirred at 0-5° C. for 1 h. To this reaction mixture wasthen added 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (290 mg, 0.93 mmol) and stirred at room temperature for 30min. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×50 mL), brine (50 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase column chromatography using50-55% acetonitrile in aqueous formic acid (0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropylphenyl)acetamide(85 mg, 0.18 mmol, 19% yield) as a pale yellow solid. MS (ESI) m/z470.21 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.60 (t, J=6.1Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.57-7.47 (m, 2H), 7.45-7.30 (m, 4H),5.10 (dd, J=5.1, 13.2 Hz, 1H), 4.48-4.22 (m, 4H), 3.02-2.84 (m, 2H),2.74-2.54 (m, 1H), 2.46-2.30 (m, 1H), 2.05-1.93 (m, 1H), 1.3-1.12 (m,6H).

Example 352-(2,4-Dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. Ethyl 2-(2,4-dichlorophenyl)-2-oxoacetate

To a stirred solution of 1-(2,4-dichlorophenyl)ethanone (3.0 g, 15.87mmol) in pyridine (20 mL) was added selenium dioxide (3.5 g, 31.74 mmol)and stirred at 100° C. for 16 h. The reaction mixture was diluted withdichloromethane (30 mL) and filtered through Celite pad. To the filtratewas added ethyl chloroformate (6 mL) at 0° C. and stirred at roomtemperature for 3 h. The reaction mixture was neutralized with 1Naqueous hydrochloric acid (up to pH-4) and extracted with ethyl acetate(2×100 mL). The combined organic layers were washed with water (2×50mL), brine (50 mL), dried over sodium sulphate and concentrated toafford ethyl 2-(2,4-dichlorophenyl)-2-oxoacetate (3.0 g, 12.19 mmol, 76%yield). ¹HNMR complies. ¹H NMR (400 MHz, DMSO-d₆) δ 7.88-7.82 (m, 2H),7.65 (d, J=8.4 Hz, 1H), 4.37 (q, J=7.0 Hz, 2H), 1.30 (t, J=7.0 Hz, 3H),

B. Ethyl 2-(2,4-dichlorophenyl)-2,2-difluoroacetate

A solution of ethyl 2-(2,4-dichlorophenyl)-2-oxoacetate (1.0 g, 4.58mmol) and diethyl amino sulfur trifluoride (3.7 g, 22.89 mmol) wasstirred at room temperature for 16 h. The reaction mixture wasneutralized with aqueous saturated sodium bicarbonate (up to pH-8) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×30 mL), brine (30 mL), dried over sodium sulphateand concentrated to afford ethyl2-(2,4-dichlorophenyl)-2,2-difluoroacetate (1.0 g, 3.73 mmol, 92%yield). GCMS (m/z) 268 [M]⁺.

C. 2-(2,4-Dichlorophenyl)-2,2-difluoroacetic acid

To a stirred solution of ethyl2-(2,4-dichlorophenyl)-2,2-difluoroacetate (1.0 g, 3.73 mmol) intetrahydrofuran:methanol:water mixture (30 mL, 1:1:1) was added lithiumhydroxide monohydrate (940.2 mg, 22.38 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous hydrochloric acid (10 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine (20 mL), dried over sodium sulphate and concentratedto afford 2-(2,4-dichlorophenyl)-2,2-difluoroacetic acid (800 mg, 3.33mmol, 89% yield. MS (ESI) m/z 241 [M+2]⁺.

D.2-(2,4-Dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a cold (0° C.) stirred solution of2-(2,4-dichlorophenyl)-2,2-difluoroacetic acid (279.6 mg, 1.165 mmol) inpyridine (10 mL) was added phosphoryl chloride (0.3 mL, 2.91 mmol) andstirred at 0-5° C. for 30 min. To this reaction mixture was then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (2×25 mL). Thecombined organic layers were washed with water (25 mL), brine (25 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase Grace column chromatographyusing 50-55% acetonitrile in aqueous formic acid (0.1%) to afford2-(2,4-Dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(60 mg, 0.12 mmol, 12% yield) as an off white solid. MS (ESI) m/z 496.03[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (m, 1H), 9.70 (t, J=6.3 Hz,1H), 7.84-7.65 (m, 3H), 7.66-7.57 (d, J=8.4 Hz, 1H), 7.50 (s, 1H), 7.44(d, J=8.0 Hz, 1H), 5.11 (dd, J=5.1, 13.2 Hz, 1H), 4.49 (br d, J=5.5 Hz,2H), 4.43 (s, 1H), 4.34 (s, 1H), 4.28 (s, 1H), 2.99-2.84 (m, 1H),2.60-2.57 (m, 1H), 2.44-2.31 (m, 1H), 2.05-1.94 (m, 1H).

Example 36N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-methoxyphenyl)acetamide

A. Ethyl 2-(2-methoxyphenyl)-2-oxoacetate

To a stirred solution of 1-(2-methoxyphenyl)ethanone (2.0 g, 13.32 mmol)in pyridine (25 mL) was added selenium dioxide (3.7 g, 33.29 mmol) andstirred for 16 h at 100° C. The reaction mixture was diluted withdichloromethane (50 mL) and filtered through Celite pad. To the filtratewas added ethyl chloroformate (6 mL) at 0° C. and stirred for 2 h. Thereaction mixture was diluted with water (30 mL) and extracted with ethylacetate (3×100 mL). The combined organic layers were washed with water(2×50 mL), brine (50 mL), dried over sodium sulphate and concentrated toafford ethyl 2-(2-methoxyphenyl)-2-oxoacetate (2.0 g, 9.62 mmol, 72%yield). GCMS (m/z) 208.2 [M]⁺.

B. Ethyl 2,2-difluoro-2-(2-methoxyphenyl)acetate

To ethyl 2-(2-methoxyphenyl)-2-oxoacetate (1.0 g, 4.81 mmol) was addeddiethyl amino sulfur trifluoride (3 mL) at 0° C. and stirred at roomtemperature for 16 h. The reaction mixture was neutralized with aqueoussaturated sodium bicarbonate (up to pH-8) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with water(2×25 mL), brine (25 mL), dried over sodium sulphate and concentrated toafford ethyl 2,2-difluoro-2-(2-methoxyphenyl)acetate (1.0 g, 4.35 mmol,90% yield). GCMS (m/z) 230.2 [M⁺].

C. 2,2-Difluoro-2-(2-methoxyphenyl)acetic acid

To a stirred solution of ethyl 2,2-difluoro-2-(2-methoxyphenyl)acetate(1.0 g, 4.35 mmol) in tetrahydrofuran:methanol:water mixture (30 mL,1:1:1) was added lithium hydroxide monohydrate (913 mg, 21.74 mmol) andstirred at room temperature for 4 h. The reaction mixture wasconcentrated and the residue was neutralized with saturated potassiumbisulphate (20 mL) and extracted with ethyl acetate (2×25 mL). Thecombined organic layers were washed with brine (25 mL), dried oversodium sulphate and concentrated to afford2,2-difluoro-2-(2-methoxyphenyl)acetic acid (700 mg, 3.46 mmol, 79%yield). MS (ESI) m/z 201.29 [M−1]⁺.

D.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-methoxyphenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(2-methoxyphenyl)acetic acid (200 mg, 0.99 mmol) inpyridine (20 mL) was added phosphoryl chloride (454 mg, 0.99 mmol)dropwise and stirred at 0-5° C. for 1 h and then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (306 mg, 0.99 mmol) and stirred at room temperature for 30min. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×50 mL), brine (50 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase column chromatography using50-55% acetonitrile in aqueous formic acid (0.1%) to giveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-methoxyphenyl)acetamide(80 mg, 0.17 mmol, 17% yield) as an off white solid. MS (ESI) m/z 458.15[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.37 (t, J=5.9 Hz,1H), 7.73 (d, J=7.7 Hz, 1H), 7.59-7.41 (m, 4H), 7.17-7.03 (m, 2H), 5.11(dd, J=5.0, 13.0 Hz, 1H), 4.53-4.26 (m, 4H), 3.66 (s, 3H), 3.01-2.85 (m,1H), 2.74-2.54 (m, 1H), 2.45-2.29 (m, 1H), 2.09-1.90 (m, 1H)

Example 372-(4-Cyclopropylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. 1-(4-Cyclopropylphenyl)ethanone

To a stirred and degassed solution of 1-(4-bromophenyl)ethanone (1 g,5.02 mmol) in water: 1,4-dioxane (1:10, 50 mL) was addedcyclopropylboronic acid (519 mg, 6.02 mmol) followed by potassiumphosphate (3.2 g, 15.07 mmol), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (II) dichloromethane complex (205 mg, 0.25 mmol). Thereaction mixture was degassed for 10 min and heated at 100° C. for 8 h.The reaction mixture was cooled to room temperature and filtered throughthe Celite pad. To the filtrate was added cold water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×50 mL), brine (50 mL), dried over sodium sulphateand concentrated. The resultant residue was purified by columnchromatography (100-200 silica) using 20% ethyl acetate in pet ether toafford 1-(4-cyclopropylphenyl)ethanone (700 mg, 4.37 mmol, 87% yield).GCMS (m/z) 160.2 [M]⁺.

B. Ethyl 2-(4-cyclopropylphenyl)-2-oxoacetate

To a stirred solution of 1-(4-cyclopropylphenyl)ethanone (700 mg, 4.37mmol) in pyridine (10 mL) was added selenium dioxide (1.2 g, 10.93 mmol)and stirred at 100° C. for 16 h. The reaction mixture was diluted withdichloromethane (20 mL) and filtered through Celite pad. To the filtratewas added ethyl chloroformate (2 mL) at 0° C. and stirred at roomtemperature for 3 h. The reaction mixture was neutralized with 1Naqueous hydrochloric acid (up to pH-4) and extracted with ethyl acetate(2×60 mL). The combined organic layers were washed with water (2×30 mL),brine (30 mL), dried over sodium sulphate and concentrated to affordethyl 2-(4-cyclopropylphenyl)-2-oxoacetate (890 mg, 4.08 mmol, 93%yield). GCMS (m/z) 218.2 [M]⁺

C. Ethyl 2-(4-cyclopropylphenyl)-2,2-difluoroacetate

A solution of ethyl 2-(4-cyclopropylphenyl)-2-oxoacetate (890 mg, 4.08mmol) and diethyl amino sulfur trifluoride (3.7 g, 22.89 mmol) wasstirred at room temperature for 16 h. The reaction mixture wasneutralized with aqueous saturated sodium bicarbonate (up to pH-8) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×30 mL), brine (30 mL), dried over sodium sulphateand concentrated to afford ethyl2-(4-cyclopropylphenyl)-2,2-difluoroacetate (920 mg, 3.83 mmol, 94%yield). GCMS (m/z) 240.2 [M]⁺

D. 2-(4-Cyclopropylphenyl)-2,2-difluoroacetic acid

To a stirred solution of ethyl2-(4-cyclopropylphenyl)-2,2-difluoroacetate (920 mg, 3.83 mmol) intetrahydrofuran-methanol-water (30 mL, 1:1:1) was added lithiumhydroxide monohydrate (483 mg, 11.49 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous hydrochloric acid (10 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine (20 mL), dried over sodium sulphate and concentratedto afford 2-(4-cyclopropylphenyl)-2,2-difluoroacetic acid (750 mg, 3.53mmol, 92% yield). GCMS (m/z) 212.1 [M]⁺.

E.2-(4-Cyclopropylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a cold (0° C.) stirred solution of2-(4-cyclopropylphenyl)-2,2-difluoroacetic acid (200 mg, 0.943 mmol) inpyridine (10 mL) was added phosphoryl chloride (0.4 mL, 2.830 mmol) andstirred at 0-5° C. for 30 min. To this reaction mixture was then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (359 mg, 1.16 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (2×25 mL). Thecombined organic layers were washed with water (25 mL), brine (25 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase column chromatography using40-45% acetonitrile in aqueous formic acid (0.1%) to afford2-(4-cyclopropylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(90 mg, 0.192 mmol, 20.0% yield) as an off white solid. MS (ESI) m/z468.13 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.58 (t, J=5.9Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.39-7.31 (m,2H), 7.21 (d, J=8.1 Hz, 2H), 5.10 (dd, J=5.1, 13.2 Hz, 1H), 4.49-4.21(m, 4H), 3.00-2.81 (m, 1H), 2.67-2.56 (m, 1H), 2.45-2.29 (m, 1H),2.07-1.92 (m, 2H), 1.04-0.97 (m, 2H), 0.55-0.77 (m, 2H).

Example 382-(4-Chloro-2-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. Ethyl 2-(4-chloro-2-fluorophenyl)-2-oxoacetate

To a stirred solution of 1-(4-chloro-2-fluorophenyl)ethanone (2.0 g,11.588 mmol) in pyridine (30 mL) was added selenium dioxide (2.57 g,23.176 mmol) and stirred for 16 h at 100° C. The reaction mixture wasdiluted with dichloromethane (30 mL) and filtered through Celite pad. Tothe filtrate was added ethyl chloroformate (4 mL) at 0° C. and stirredfor 2 h. To the reaction mixture was added water (30 mL) and extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith water (2×20 mL), brine (20 mL), dried over sodium sulphate andconcentrated. The resultant residue was purified by columnchromatography (100-200 silica) using 5-10% ethyl acetate in petroleumether to afford ethyl 2-(4-chloro-2-fluorophenyl)-2-oxoacetate (1.71 g,7.434 mmol, 64% yield) as a colourless liquid. MS (ESI) m/z. 230.1.

B. Ethyl 2-(4-chloro-2-fluorophenyl)-2,2-difluoroacetate

Ethyl 2-(4-chloro-2-fluorophenyl)-2-oxoacetate (1.71 g, 7.434 mmol) wasreacted with diethylaminosulfur trifluoride (2.45 mL, 18.585 mmol) andstirred for 12 h at room temperature. The reaction mixture wasneutralized with aqueous saturated sodium bicarbonate (up to pH-8) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×10 mL), brine (10 mL), dried over sodium sulphateand concentrated to afford ethyl2-(4-chloro-2-fluorophenyl)-2,2-difluoroacetate (1.0 g, 4.087 mmol, 55%yield) as a colorless liquid. MS (ESI) m/z. 252.1.

C. 2-(4-Chloro-2-fluorophenyl)-2,2-difluoroacetic acid

To a cold (0° C.) stirred solution of ethyl2-(4-chloro-2-methylphenyl)-2,2-difluoroacetate (1.0 g, 4.087 mmol) intetrahydrofuran:ethanol:water mixture (30 mL, 1:1:1) was added lithiumhydroxide monohydrate (0.85 g, 20.436 mmol) and stirred at roomtemperature for 6 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous hydrochloric acid (10 mL) andextracted with ethyl acetate (2×20 mL). The combined organic layers werewashed with brine (20 mL), dried over sodium sulphate and concentratedto 2-(4-chloro-2-fluorophenyl)-2,2-difluoroacetic acid (550 mg, 2.455mmol, 62% yield) as an brown solid. MS (ESI) m/z. 224.0.

D.2-(4-Chloro-2-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a cold (0° C.) stirred solution of2-(4-chloro-2-fluorophenyl)-2,2-difluoroacetic acid (217 mg, 0.968 mmol)in pyridine was added phosphorus oxychloride (0.27 mL, 2.906 mmol)dropwise and stirred at 0-5° C. for 1 h. To this reaction mixture wasadded 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.968 mmol) and stirred at room temperature for30 min. The reaction mixture was neutralized with aqueous saturatedsodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with water (2×10 mL), brine(10 mL), dried over sodium sulphate and concentrated. The resultantresidue was purified by Reveleris C-18 reversed phase columnchromatography using 40-55% acetonitrile in aqueous formic acid (0.1%)to give2-(4-chloro-2-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(59 mg, 0.123 mmol, 12% yield) as an off white solid. MS (ESI) m/z480.07 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.74 (s, 1H),7.69 (dd, J=11.1, 7.8 Hz, 3H), 7.55-7.29 (m, 3H), 5.16-5.09 (dd, J=5.1Hz, 1H), 4.52-4.27 (m, 4H), 3.00-2.84 (m, 1H), 2.66-2.55 (m, 1H),2.41-2.30 (m, 1H), 2.04-1.94 (m, 1H).

Example 392-(4-Chloro-3-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. Ethyl 2-(4-chloro-3-fluorophenyl)-2-oxoacetate

To a stirred solution of 1-(4-chloro-3-fluorophenyl)ethanone (2.0 g,11.62 mmol) in pyridine (20 mL) was added selenium dioxide (2.5 g, 23.25mmol) and stirred at 100° C. for 16 h. The reaction mixture was dilutedwith dichloromethane (30 mL) and filtered through Celite pad. To thefiltrate was added ethyl chloroformate (6 mL) at 0° C. and stirred atroom temperature for 3 h. The reaction mixture was neutralized with 1Naqueous hydrochloric acid (up to pH-4) and extracted with ethyl acetate(2×100 mL). The combined organic layers were washed with water (2×50mL), brine (50 mL), dried over sodium sulphate and concentrated toafford ethyl 2-(4-chloro-3-fluorophenyl)-2-oxoacetate (2.0 g, 8.69 mmol,75% yield). GCMS (m/z) 230 [M]⁺.

B. Ethyl 2-(4-chloro-3-fluorophenyl)-2,2-difluoroacetate

A solution of ethyl 2-(4-chloro-3-fluorophenyl)-2-oxoacetate (1.0 g,4.34 mmol) and diethyl amino sulfur trifluoride (3.7 g, 22.89 mmol) wasstirred at room temperature for 16 h. The reaction mixture wasneutralized with aqueous saturated sodium bicarbonate (up to pH-8) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×30 mL), brine (30 mL), dried over sodium sulphateand concentrated to afford ethyl2-(4-chloro-3-fluorophenyl)-2,2-difluoroacetate (900 mg, 3.57 mmol, 82%yield). GCMS (m/z) 252.1 [M]⁺.

C. 2-(4-Chloro-3-fluorophenyl)-2,2-difluoroacetic acid

To a stirred solution of ethyl2-(4-chloro-3-fluorophenyl)-2,2-difluoroacetate (800 mg, 3.17 mmol) intetrahydrofuran:methanol:water mixture (20 mL, 1:1:1) was added lithiumhydroxide monohydrate (798 mg, 19.04 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous hydrochloric acid (10 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine (20 mL), dried over sodium sulphate and concentratedto afford 2-(4-chloro-3-fluorophenyl)-2,2-difluoroacetic acid (600 mg,2.67 mmol, 84% yield. MS (ESI) m/z 223.1 [M−1]⁺.

D.2-(4-Chloro-3-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a cold (0° C.) stirred solution of2-(4-chloro-3-fluorophenyl)-2,2-difluoroacetic acid (261 mg, 1.165 mmol)in pyridine (10 mL) was added phosphoryl chloride (0.3 mL, 2.91 mmol)and stirred at 0-5° C. for 30 min. To this reaction mixture was thenadded 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (2×25 mL). Thecombined organic layers were washed with water (25 mL), brine (25 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase Grace column chromatographyusing 50-55% acetonitrile in aqueous formic acid (0.1%) to afford2-(4-Chloro-3-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(50 mg, 0.10 mmol, 11% yield) as an off white solid. MS (ESI) m/z 480.05[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.70 (br s, 1H), 7.81(br t, J=7.9 Hz, 1H), 7.71-7.60 (m, 2H), 7.49-7.32 (m, 3H), 5.10 (br dd,J=5.1, 13.2 Hz, 1H), 4.49-4.38 (m, 3H), 4.34-4.25 (m, 1H), 2.99-2.83 (m,1H), 2.63-2.56 (br s, 1H), 2.44-2.26 (m, 1H), 2.06-1.94 (m, 1H).

Example 40N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-fluoro-2-methylphenyl)acetamide

A. 1-(3-Fluoro-2-methylphenyl)ethanone

To a stirred solution of 3-fluoro-2-methylbenzonitrile (3 g, 22.22 mmol)in benzene (20 mL) was added methyl magnesium iodide (9.0 mL, 26.64mmol, 3M in diethyl ether) at 0° C. and stirred at 80° C. for 8 h. Thenthe reaction mixture was cooled to room temperature, added 6Nhydrochloric acid (25 mL) and stirred at heated 80° C. for 8 h. Thereaction mixture was cooled to room temperature and extracted with ethylacetate (3×100 mL). The combined organic layers were washed with water(2×100 mL), brine (100 mL), dried over sodium sulphate and concentratedto afford 1-(3-fluoro-2-methylphenyl)ethanone (920 mg, 6.05 mmol, 27%yield). GCMS (m/z) 152.2 [M]⁺

B. Ethyl 2-(3-fluoro-2-methylphenyl)-2-oxoacetate

To a stirred solution of 1-(3-fluoro-2-methylphenyl)ethanone (900 mg,5.91 mmol) in pyridine (25 mL) was added selenium dioxide (1.7 g, 14.79mmol) and stirred for 12 h at 100° C. The reaction mixture was dilutedwith dichloromethane (20 mL) and filtered through Celite pad. To thefiltrate was added ethyl chloroformate (3 mL) at 0° C. and stirred atroom temperature for 2 h. The reaction mixture was neutralized with 1Naqueous hydrochloric acid (up to pH-4) and extracted with ethyl acetate(3×50 mL). The combined organic layers were washed with water (2×50 mL),brine (50 mL), dried over sodium sulphate and concentrated to affordethyl 2-(3-fluoro-2-methylphenyl)-2-oxoacetate (1.2 g, 5.71 mmol, 96%).GCMS (m/z) 210.2 [M]⁺

C. Ethyl 2,2-difluoro-2-(3-fluoro-2-methylphenyl)acetate

A solution of ethyl 2-(3-fluoro-2-methylphenyl)-2-oxoacetate (1.2 g,5.71 mmol) and diethyl amino sulfur trifluoride (4.3 g, 26.67 mmol) werestirred at room temperature for 16 h. The reaction mixture wasneutralized with aqueous saturated sodium bicarbonate (up to pH-8) andextracted with ethyl acetate (3×50 mL). The combined organic layer waswashed with water (2×50 mL), brine (50 mL), dried over sodium sulphateand concentrated to afford ethyl2,2-difluoro-2-(3-fluoro-2-methylphenyl)acetate (1.0 g, 4.31 mmol, 76%)as a brown liquid. GCMS (m/z) 232.2 [M]⁺

D. 2,2-Difluoro-2-(3-fluoro-2-methylphenyl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(3-fluoro-2-methylphenyl)acetate (1.0 g, 4.31 mmol) in inmethanol:tetrahydrofuran:water (1:1:1, 30 mL) was added lithiumhydroxide monohydrate (543 mg, 12.93 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous hydrochloric acid (10 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine (50 mL), dried over sodium sulphate and concentratedto afford 2,2-difluoro-2-(3-fluoro-2-methylphenyl)acetic acid (800 mg,3.92 mmol, 91% yield). GCMS (m/z) 204.1 [M]⁺

E.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-fluoro-2-methylphenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(3-fluoro-2-methylphenyl)acetic acid (200 mg, 0.98 mmol)in pyridine (10 mL) was added phosphoryl chloride (0.3 mL, 2.94 mmol)dropwise and stirred at 0-5° C. for 30 min. To this reaction mixture wasthen added 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (303 mg, 0.98 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (2×25 mL). Thecombined organic layers were washed with water (25 mL), brine (25 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase column chromatography using40-45% acetonitrile in aqueous formic acid (0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-fluoro-2-methylphenyl)acetamide(80 mg, 0.17 mmol, 18.0% yield) as an off white solid. MS (ESI) m/z460.10 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.68 (t, J=5.9Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.49-7.31 (m, 5H), 5.10 (dd, J=4.8,13.2 Hz, 1H), 4.52-4.22 (m, 4H), 3.00-2.82 (m, 1H), 2.67-2.54 (m, 1H),2.46-2.30 (m, 1H), 2.21 (br s, 3H), 2.09-1.92 (m, 1H).

Example 412-(3-Chloro-2-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. 1-(3-Chloro-2-methylphenyl)ethanone

To a stirred solution of 3-chloro-2-methylbenzonitrile (2.0 g, 13.245mmol) in benzene (30 mL) was added methyl magnesium iodide (3M) indiethyl ether solution (5.3 mL, 15.89 mmol) at 0° C. and stirred for 16h at 75° C. The reaction mixture was treated with 6N aqueoushydrochloric acid solution (20 mL) at 0° C. and stirred for 4 h at 75°C. The reaction mixture was quenched with water (50 mL) and extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith water (2×20 mL), brine (20 mL), dried over sodium sulphate andconcentrated. The obtained residue was purified by column chromatography(100-200 silica) using 5-8% ethyl acetate in petroleum ether to afford1-(4-chloro-2-methylphenyl)ethanone (1.4 g, 8.333 mmol, 63% yield) as acolorless liquid. GCMS (ESI) m/z. 168.1.

B. Ethyl 2-(3-chloro-2-methylphenyl)-2-oxoacetate

To a stirred solution of 1-(4-chloro-2-methylphenyl)ethanone (1.4 g,8.333 mmol) in pyridine (30 mL) at 0° C., was added selenium dioxide(1.85 g, 16.666 mmol) and stirred for 16 h at 100° C. The reactionmixture was diluted with dichloromethane (30 mL) and filtered throughCelite pad. To the filtrate was added ethyl chloroformate (3 mL) at 0°C. and stirred for 2 h. The reaction mixture quenched with water andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×20 mL), brine (20 mL), dried over sodium sulphateand concentrated. The resultant residue was purified by columnchromatography (100-200 silica) using 5-10% ethyl acetate in pet. etherto give ethyl 2-(3-chloro-2-methylphenyl)-2-oxoacetate (1.1 g, 4.867mmol, 58.5% yield) as a colorless liquid. GCMS (ESI) m/z. 226.1.

C. Ethyl 2-(3-chloro-2-methylphenyl)-2,2-difluoroacetate

To ethyl 2-(3-chloro-2-methylphenyl)-2-oxoacetate (1.1 g, 4.867 mmol)was added diethyl amino sulfur trifluoride (1.6 mL, 12.168 mmol) andstirred for 12 h at room temperature. The reaction mixture wasneutralized with aqueous saturated sodium bicarbonate (up to pH-8) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×10 mL), brine (10 mL), dried over sodium sulphateand concentrated to afford ethyl2-(3-chloro-2-methylphenyl)-2,2-difluoroacetate (710 mg, 2.862 mmol, 58%yield) as a colourless liquid. GCMS (ESI) m/z. 248.1.

D. 2-(3-Chloro-2-methylphenyl)-2,2-difluoroacetic acid

To a cold (0° C.) stirred solution of ethyl2-(3-chloro-2-methylphenyl)-2,2-difluoroacetate (710 mg, 2.862 mmol) intetrahydrofuran:ethanol:water mixture (30 mL, 1:1:1) was added lithiumhydroxide (0.6 g, 14.314 mmol) and stirred at room temperature for 6 h.The reaction mixture was concentrated and the residue was neutralizedwith 10% aqueous hydrochloric acid (10 mL) and extracted with ethylacetate (2×30 mL). The combined organic layers were washed with brine(20 mL), dried over sodium sulphate and concentrated to afford2-(3-chloro-2-methylphenyl)-2,2-difluoroacetic acid (382 g, 1.736 mmol,60% yield) as an solid. MS (ESI) m/z 219.17 [M−1]⁻.

E.2-(3-Chloro-2-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a cold (0° C.) stirred solution of2-(3-chloro-2-methylphenyl)-2,2-difluoroacetic acid (213 mg, 0.968 mmol)in pyridine was added phosphorus oxychloride (0.27 mL, 2.906 mmol)dropwise and stirred at 0-5° C. for 1 h and then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.968 mmol) and stirred at room temperature for30 min. The reaction mixture was neutralized with aqueous saturatedsodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3×50mL). The combined organic layer was washed with water (2×10 mL), brine(10 mL) and dried over sodium sulphate and concentrated. The resultantresidue was purified by Reveleris C-18 reversed phase columnchromatography using 40-55% acetonitrile in aqueous formic acid (0.1%)to afford2-(3-chloro-2-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(62 mg, 0.130 mmol, 13% yield) as white solid. MS (ESI) m/z 476.07[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.68 (s, 1H), 7.68(dd, J=15.3, 7.9 Hz, 2H), 7.55 (d, J=7.3 Hz, 1H), 7.46 (s, 1H),7.44-7.34 (m, 2H), 5.11 (dd, J=13.3, 5.0 Hz, 1H), 4.52-4.27 (m, 4H),3.00-2.84 (m, 1H), 2.66-2.55 (m, 1H), 2.43-2.30 (m, 4H), 2.04-1.94 (m,1H).

Example 42N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-(trifluoromethyl)phenyl)acetamide

A. Ethyl 2,2-difluoro-2-(4-fluoro-2-(trifluoromethyl)phenyl)acetate

To a stirred solution of 4-fluoro-1-iodo-2-(trifluoromethyl)benzene (500mg, 1.72 mmol) in dimethylsulfoxide (5.2 mL) was added copper (329 mg,5.17 mmol) and ethyl 2-bromo-2,2-difluoroacetate (418 mg, 2.07 mmol) atroom temperature and stirred at 55° C. for 16 h. The reaction mixturewas neutralized with aqueous saturated ammonium chloride solution andextracted with ethyl acetate (3×25 mL). The combined organic layers werewashed with water (2×25 mL), brine (25 mL), dried over sodium sulphateand concentrated to afford ethyl2,2-difluoro-2-(4-fluoro-2-(trifluoromethyl)phenyl)acetate (300 mg, 1.05mmol, 61%). 1H NMR (400 MHz, CDCl₃) δ 7.87-7.83 (m, 1H), 7.51-7.48 (m,1H), 7.39-7.34 (m, 1H), 4.35-4.30 (m, 2H), 1.30 (t, J=5.1 Hz, 3H).

B. 2,2-Difluoro-2-(4-fluoro-2-(trifluoromethyl)phenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(4-fluoro-2-(trifluoromethyl)phenyl)acetate (300 mg, 1.05mmol) in tetrahydrofuran:methanol:water mixture (15 mL, 1:1:1) was addedlithium hydroxide (132 mg, 3.15 mmol) and stirred at room temperaturefor 4 h. The reaction mixture was concentrated and the residue wasneutralized with saturated potassium bisulphate (20 mL) and extractedwith ethyl acetate (2×25 mL). The combined organic layers were washedwith brine (25 mL), dried over sodium sulphate and concentrated toafford 2,2-difluoro-2-(4-fluoro-2-(trifluoromethyl)phenyl)acetic acid(220 mg, 0.85 mmol, 81% yield). MS (ESI) m/z 257.1[M−1]⁺.

C.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-(trifluoromethyl)phenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(4-fluoro-2-(trifluoromethyl)phenyl)acetic acid (200 mg,0.78 mmol) in pyridine (20 mL) was added phosphoryl chloride (356 mg,2.32 mmol) dropwise and stirred at 0-5° C. for 1 h and then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (302 mg, 0.78 mmol) and stirred at room temperature for 30min. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×50 mL), brine (50 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase column chromatography using55-60% acetonitrile in aqueous formic acid (0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-(trifluoromethyl)phenyl)acetamide(75 mg, 0.17 mmol, 21% yield) as a white solid. MS (ESI) m/z 514.07[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ=10.98 (s, 1H), 9.73-9.62 (m, 1H),7.96-7.82 (m, 2H), 7.78-7.67 (m, 2H), 7.49-7.37 (m, 2H), 5.11 (dd,J=4.8, 13.2 Hz, 1H), 4.53-4.26 (m, 4H), 3.00-2.82 (m, 1H), 2.77-2.54 (m,1H), 2.44-2.23 (m, 1H), 2.08-1.93 (m, 1H)

Example 432-(4-Chloro-2-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. 1-(4-Chloro-2-methylphenyl)ethanone

To a stirred solution of 4-chloro-2-methylbenzonitrile (2.0 g, 13.193mmol) in benzene (30 mL) was added methyl magnesium iodide (3M) indiethyl ether solution (5.27 mL, 15.83 mmol) at 0° C. and stirred for 16h at 75° C. The reaction mixture was cooled to 0° C. and quenched with6N hydrochloric acid solution (20 mL) and continued to stir at 75° C.for 4 h. The reaction mixture was quenched with water and extracted withethyl acetate (3×50 mL). The combined organic layers were washed withwater (2×20 mL), brine (20 mL), dried over sodium sulphate andconcentrated. The obtained residue was purified by column chromatography(100-200 silica) using 5-10% ethyl acetate in petroleum ether to afford1-(4-chloro-2-methylphenyl)ethanone (1.5 g, 8.928 mmol, 67% yield) as acolorless liquid. GCMS (ESI) m/z. 168.1.

B. Ethyl 2-(4-chloro-2-methylphenyl)-2-oxoacetate

To a stirred solution of 1-(4-chloro-2-methylphenyl)ethanone (1.5 g,8.928 mmol) in pyridine (30 mL) was added selenium dioxide (2 g, 17.857mmol) and stirred for 16 h at 100° C. The reaction mixture was cooled toroom temperature, diluted with dichloromethane (30 mL) and filteredthrough Celite pad. To the filtrate was added ethyl chloroformate (3 mL)at 0° C. and stirred for 2 h. The reaction mixture was quenched withwater and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with water (2×20 mL), brine (20 mL), dried oversodium sulphate and concentrated. The obtained residue was purified bycolumn chromatography (100-200 silica) using 5-10% ethyl acetate in pet.ether to afford ethyl 2-(4-chloro-2-methylphenyl)-2-oxoacetate (1.1 g,4.867 mmol, 54% yield) as a colorless liquid. MS (ESI) m/z. 226.2.

C. Ethyl 2-(4-chloro-2-methylphenyl)-2,2-difluoroacetate

To ethyl 2-(4-chloro-2-methylphenyl)-2-oxoacetate (1.1 g, 4.867 mmol)was added diethylaminosulfur trifluoride (1.6 mL, 12.168 mmol) andstirred for 12 h at room temperature. The reaction mixture wasneutralized with aqueous saturated sodium bicarbonate (up to pH-8) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×10 mL), brine (10 mL), dried over sodium sulphateand concentrated to afford ethyl2-(4-chloro-2-methylphenyl)-2,2-difluoroacetate (692 mg, 2.790 mmol, 57%yield) as a colorless liquid. GCMS (ESI) m/z. 248.1.

D. 2-(4-Chloro-2-methylphenyl)-2,2-difluoroacetic acid

To a cold (0° C.) stirred solution of ethyl2-(4-chloro-2-methylphenyl)-2,2-difluoroacetate (692 mg, 2.790 mmol) intetrahydrofuran:ethanol:water mixture (30 mL, 1:1:1) was added lithiumhydroxide (585 mg, 13.951 mmol) and stirred at room temperature for 6 h.The reaction mixture was concentrated and the residue was neutralizedwith 10% aqueous hydrochloric acid (10 mL) and extracted with ethylacetate (2×20 mL). The combined organic layers were washed with brine(20 mL), dried over sodium sulphate and concentrated to afford2-(4-chloro-2-methylphenyl)-2,2-difluoroacetic acid (446 g, 2.027 mmol,72% yield) as an brown liquid. MS (ESI) m/z 219.29 [M−1]⁻.

E.2-(4-Chloro-2-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a cold (0° C.) stirred solution of2-(4-chloro-2-methylphenyl)-2,2-difluoroacetic acid (213 mg, 0.968 mmol)in pyridine was added phosphorus oxychloride (0.27 mL, 2.906 mmol)dropwise and stirred at 0-5° C. for 1 h and then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.968 mmol) and stirred at room temperature for30 min. The reaction mixture was neutralized with aqueous saturatedsodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with water (2×10 mL), brine(10 mL), dried over sodium sulphate and concentrated. The obtainedresidue was purified by Reveleris C-18 reversed phase columnchromatography using 40-60% acetonitrile in aqueous formic acid (0.1%)to afford2-(4-chloro-2-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(90 mg, 0.189 mmol, 19.5% yield) as an off white solid. MS (ESI) m/z476.09 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.65 (t, J=5.9Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.50-7.31 (m,4H), 5.11 (dd, J=13.2, 5.1 Hz, 1H), 4.52-4.25 (m, 4H), 3.00-2.85 (m,1H), 2.65-2.55 (m, 1H), 2.45-2.31 (m, 4H), 2.08-1.94 (m, 1H).

Example 44N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-methylphenyl)acetamide

A. 1-(4-Fluoro-2-methylphenyl)ethanone

To a stirred solution of 4-fluoro-2-methylbenzonitrile (2.0 g, 14.803mmol) in benzene (30 mL) was added methyl magnesium iodide (3M) indiethyl ether solution (5.92 mL, 17.764 mmol) at 0° C. and stirred for16 h at 75° C. The reaction mixture was cooled to 0° C. and quenchedwith 6N hydrochloric acid solution (20 mL) and continued to stir at 75°C. for 4 h. The reaction mixture was quenched with water and extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith water (2×20 mL), brine (20 mL), dried over sodium sulphate andconcentrated. The residue obtained was purified by column chromatography(100-200 silica) using 5-10% ethyl acetate in petroleum ether to afford1-(4-fluoro-2-methylphenyl)ethanone (1.6 g, 10.526 mmol, 71% yield) as acolourless liquid. GCMS (ESI) m/z. 152.2.

B. Ethyl 2-(4-fluoro-2-methylphenyl)-2-oxoacetate

To a stirred solution of 1-(4-fluoro-2-methylphenyl)ethanone (1.6 g,10.526 mmol) in pyridine (30 mL) was added selenium dioxide (2.3 g,21.052 mmol) and stirred for 16 h at 100° C. The reaction mixture wascooled to room temperature, diluted with dichloromethane (30 mL) andfiltered through Celite pad. To the filtrate was added ethylchloroformate (3.2 mL) at 0° C. and stirred for 2 h. The reactionmixture was quenched with water and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with water (2×20 mL), brine(20 mL), dried over sodium sulphate and concentrated. Obtained residuewas purified by column chromatography (100-200 silica) using 5-10% ethylacetate in petether to afford ethyl2-(4-fluoro-2-methylphenyl)-2-oxoacetate (1.37 g, 6.523 mmol, 62% yield)as a colourless liquid. GCMS (ESI) m/z. 210.1.

C. Ethyl 2,2-difluoro-2-(4-fluoro-2-methylphenyl)acetate

To ethyl 2-(4-chloro-2-methylphenyl)-2-oxoacetate (1.37 g, 6.523 mmol)was added diethylaminosulfur trifluoride (2.1 mL, 16.307 mmol) andstirred for 12 h at room temperature. The reaction mixture wasneutralized with aqueous saturated sodium bicarbonate (up to pH-8) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×20 mL), brine (20 mL), dried over sodium sulphateand concentrated to afford ethyl2,2-difluoro-2-(4-fluoro-2-methylphenyl)acetate (860 mg, 3.706 mmol, 57%yield) as a colourless liquid. GCMS (ESI) m/z. 232.2.

D. 2,2-Difluoro-2-(4-fluoro-2-methylphenyl)acetic acid

To a cold (0° C.) stirred solution of ethyl2-(4-chloro-2-methylphenyl)-2,2-difluoroacetate (860 mg, 3.706 mmol) intetrahydrofuran:ethanol:water mixture (30 mL, 1:1:1) was added lithiumhydroxide monohydrate (933 mg, 22.241 mmol) and stirred at roomtemperature for 6 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous hydrochloric acid (10 mL) andextracted with ethyl acetate (2×20 mL). The combined organic layers werewashed with brine (20 mL), dried over sodium sulphate and concentratedto afford 2,2-difluoro-2-(4-fluoro-2-methylphenyl)acetic acid (684 g,2.948 mmol, 72% yield) as an brown liquid. LCMS (ESI) m/z 203.37[M−1]^(−ve).

E.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-methylphenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(4-fluoro-2-methylphenyl)acetic acid (197 mg, 0.968 mmol)in pyridine was added phosphorus oxychloride (0.27 mL, 2.906 mmol)dropwise and stirred at 0-5° C. for 1 h. To this reaction mixture wasthen added 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.968 mmol) and stirred at room temperature for30 min. The reaction mixture was neutralized with aqueous saturatedsodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with water (2×10 mL), brine(10 mL), dried over sodium sulphate and concentrated. The residueobtained was purified by Reveleris C-18 reversed phase columnchromatography using 50-60% acetonitrile in aqueous formic acid (0.1%)to affordN-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-methylphenyl)acetamide(79 mg, 0.172 mmol, 18% yield) as an off white solid. MS (ESI) m/z460.10 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.63 (t, J=6.0Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.56 (dd, J=8.7, 5.8 Hz, 1H), 7.46 (s,1H), 7.40 (d, J=7.6 Hz, 1H), 7.25-7.11 (m, 2H), 5.11 (dd, J=13.3, 5.0Hz, 1H), 4.50-4.27 (m, 4H), 2.98-2.86 (m, 1H), 2.68-2.55 (m, 1H),2.46-2.28 (m, 4H), 2.08-1.94 (m, 1H).

Example 452-(4-Chloro-2-(trifluoromethyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. Ethyl 2-(4-chloro-2-(trifluoromethyl)phenyl)-2,2-difluoroacetate

To a stirred solution of 4-chloro-1-iodo-2-(trifluoromethyl)benzene (1.0g, 3.26 mmol) in dimethylsulfoxide (15 mL) was added copper (539 mg,8.48 mmol) and ethyl 2-bromo-2,2-difluoroacetate (994 mg, 4.89 mmol) atroom temperature and stirred at 55° C. for 16 h. The reaction mixturewas neutralized with aqueous saturated ammonium chloride solution andextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with water (2×100 mL), brine (100 mL), dried over sodiumsulphate and concentrated to afford ethyl2-(4-chloro-2-(trifluoromethyl)phenyl)-2,2-difluoroacetate (900 mg, 2.98mmol, 91%). GCMS (m/z) 302.0 [M]⁺.

B. 2-(4-Chloro-2-(trifluoromethyl)phenyl)-2,2-difluoroacetic acid

To a stirred solution of ethyl2-(4-chloro-2-(trifluoromethyl)phenyl)-2,2-difluoroacetate (900 mg, 2.98mmol) in tetrahydrofuran:methanol:water (15 mL, 1:1:1) was added lithiumhydroxide (375 mg, 8.94 mmol) and stirred at room temperature for 4 h.The reaction mixture was concentrated and the residue was neutralizedwith saturated potassium hydrogen sulphate (20 mL) and extracted withethyl acetate (2×100 mL). The combined organic layers were washed withbrine (100 mL), dried over sodium sulphate and concentrated to afford2-(4-chloro-2-(trifluoromethyl)phenyl)-2,2-difluoroacetic acid (700 mg,2.55 mmol, 86% yield). GCMS (m/z) 274.1 [M]⁺.

C.2-(4-Chloro-2-(trifluoromethyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a cold (0° C.) stirred solution of2-(4-chloro-2-(trifluoromethyl)phenyl)-2,2-difluoroacetic acid (200 mg,0.72 mmol) in pyridine (10 mL) was added phosphoryl chloride (336 mg,2.18 mmol) dropwise and stirred at 0-5° C. for 1 h. and then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (226 mg, 0.72 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×50 mL), brine (50 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase column chromatography using80-90% acetonitrile in aqueous formic acid (0.1%) to afford2-(4-chloro-2-(trifluoromethyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(80 mg, 0.11 mmol, 21% yield) as an off-white solid. LCMS (ESI) m/z530.05 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.70 (br t,J=5.9 Hz, 1H), 8.03 (s, 1H), 7.97 (br d, J=8.4 Hz, 1H), 7.85 (d, J=9 Hz,1H), 7.70 (d, J=7.7 Hz, 1H), 7.47 (s, 1H), 7.41 (br d, J=7.7 Hz, 1H),5.11 (br dd, J=4.8, 13.2 Hz, 1H), 4.53-4.25 (m, 4H), 3.01-2.82 (m, 1H),2.67-2.54 (m, 1H), 2.48-2.30 (m, 1H), 2.08-1.94 (m, 1H)

Example 462-Cyclohexyl-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. Ethyl 2-cyclohexyl-2,2-difluoroacetate

Ethyl-2-cyclohexyl-2-oxoacetate (1 g, 5.43 mmol) was added intodiethylamino sulfur trifluoride (2.5 mL) at 0° C. and stirred at roomtemperature for 16 h. The reaction mixture was quenched with aqueoussodium bicarbonate solution and extracted with ethyl acetate (3×20 mL).The combined organic layers were washed with brine (20 mL), dried oversodium sulphate, filtered and solvent was evaporated. Obtained crude waspurified by column chromatography (100-200 silica gel, 10% ethyl acetatein pet ether) to afford ethyl 2-cyclohexyl-2,2-difluoroacetate (900 mg,4.36 mmol, 80% yield) as a colourless liquid. ¹H NMR (300 MHz, CDCl₃)4.32 (q, J=6.9 Hz, 2H), 2.06-2.04 (m, 1H), 1.80-1.60 (m, 6H), 1.37-1.30(m, 4H), 1.26-1.19 (m, 3H).

B. 2-Cyclohexyl-2,2-difluoroacetic acid

To a stirred solution of ethyl 2-cyclohexyl-2,2-difluoroacetate (900 mg,4.36 mmol) in mixture of tetrahydrofuran:ethanol:water (15 mL, 1:1:1),was added lithium hydroxide monohydrate (550 mg, 13.10 mmol) and stirredat room temperature for 16 h. The volatiles were evaporated underreduced pressure and the resultant residue was dissolved in water (15mL) and washed with ethyl acetate (2×15 mL). Aqueous layer was acidifiedwith 1N hydrochloride aqueous solution and extracted with ethyl acetate(3×20 mL). The combined organic layers were washed with brine (20 mL),dried over sodium sulphate, filtered and solvent was evaporated toafford 2-cyclohexyl-2,2-difluoroacetic acid (550 mg, 3.08 mmol, 70%yield) as semi-solid compound. MS (ESI) m/z 178 [M]⁺.

C.2-Cyclohexyl-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To an ice cold solution of 2-cyclohexyl-2,2-difluoroacetic acid (207 mg,1.16 mmol) in pyridine (6 mL) was added phosphorus oxychloride (0.27 mL,2.9 mmol) dropwise and stirred at 0-5° C. for 1 h. Then, the reactionmixture was treated with3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) and stirred at room temperature for 2h. The reaction mixture was basified with aqueous saturated sodiumbicarbonate solution and extracted with ethyl acetate (3×15 mL). Thecombined organic layers were washed with water (15 mL), brine (15 mL),dried over sodium sulphate, filtered and solvent was evaporated. Theresultant residue was purified by Reveleris C-18 reversed phase columnchromatography (50-55% acetonitrile in 0.1% aqueous formic acid) toafford2-cyclohexyl-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro acetamide (53 mg, 0.122 mmol, 12% yield) as white solid. MS (ESI)m/z 434.07 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.35 (t,J=6.0 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J=7.8 Hz,1H), 5.11 (dd, J=13.2, 5.4 Hz, 1H), 4.45 (d, J=16.8 Hz, 1H), 4.44 (d,J=6.6 Hz, 2H), 4.31 (d, J=17.7 Hz, 1H), 2.93-2.85 (m, 1H), 2.63-2.56 (m,1H), 2.45-2.36 (m, 1H), 2.10-1.97 (m, 2H), 1.74-1.64 (m, 5H), 1.23-1.08(m, 5H).

Example 472-(4-Chloro-2-(trifluoromethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. 4-Chloro-1-iodo-2-(trifluoromethoxy)benzene

To a solution of 4-chloro-2-(trifluoromethoxy)aniline (2 g, 10.025 mmol)in 66% aqueous sulfuric acid (10 mL) was added a solution of sodiumnitrite (760 mg, 11.027 mmol) in water (2 mL) at 0° C. and stirred at 0°C. for 20 min. Then a solution of urea (90 mg, 1.5 mmol) in water (1 mL)was added at 0° C. and stirred at same temperature for 10 min. Then asolution of potassium iodide (3.49 g, 21.052 mmol) in water (5 mL) wasadded at 0° C. and stirred at 50° C. for 2 h. To the reaction mixturewas added ethyl acetate (300 mL) and washed with water (2×100 mL), brine(100 mL) and dried over sodium sulphate, and concentrated. The resultantresidue was purified by silica gel (100-200) chromatography usingpentane as eluent to afford the4-chloro-1-iodo-2-(trifluoromethoxy)benzene (2.1 g, 6.52 mmol, 69%yield) as a colorless syrup. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.79 (d,J=8.8 Hz, 1H), 7.32-7.26 (m, 1H), 7.05 (dd, J=2.4, 8.3 Hz, 1H).

B. Ethyl 2-(4-chloro-2-(trifluoromethoxy)phenyl)-2,2-difluoroacetate

To a stirred solution of 4-fluoro-1-iodo-2-(trifluoromethyl)benzene (2.1g, 6.525 mmol) in dimethyl sulfoxide (10 mL) was added copper powder(1.03 g, 16.31 mmol) and ethyl 2-bromo-2,2-difluoroacetate (1.25 mL,9.78 mmol) at room temperature and stirred at 60° C. for 16 h. Thereaction mixture was neutralized with aqueous saturated ammoniumchloride solution and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×50 mL), brine (25 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by silica gel (100-200) chromatography using 5% diethyl etherin pentane as eluent to afford ethyl2-(4-chloro-2-(trifluoromethoxy)phenyl)-2,2-difluoroacetate (1.8 g, 5.66mmol, 87%). 1H NMR (300 MHz, CDCl₃) δ (ppm) 7.70 (d, J=8.4 Hz, 1H),7.44-7.32 (m, 2H), 4.34 (q, J=7.3 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).

C. 2-(4-Chloro-2-(trifluoromethoxy)phenyl)-2,2-difluoroacetic acid

To a stirred solution of2-(4-chloro-2-(trifluoromethoxy)phenyl)-2,2-difluoroacetate (1.8 g, 6.14mmol) in tetrahydrofuran:methanol:water mixture (15 mL, 1:1:1) was addedlithium hydroxide monohydrate (774 mg, 18.42 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with saturated potassium bisulphate (20 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine (25 mL), dried over sodium sulphate and concentratedto afford 2-(4-chloro-2-(trifluoromethoxy)phenyl)-2,2-difluoroaceticacid (1.2 g, 4.137 mmol, 73% yield). MS (ESI) m/z 289.14[M−1]⁺.

D.2-(4-Chloro-2-(trifluoromethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a cold (0° C.) stirred solution of3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) and2-(4-chloro-2-(trifluoromethoxy)phenyl)-2,2-difluoroacetic acid (280 mg,0.97 mmol) in N,N-dimethylformamide (10 mL) was addedN,N-diisopropylethylamine (375 mg, 2.91 mmol) followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (480 mg, 1.26 mmol) and continued stirring atroom temperature for 16 h. The reaction mixture was diluted with water(100 mL) and the solid obtained was filtered, washed with diethyl ether(20 mL), dried and purified using silica gel chromatography (3% methanolin chloroform) to afford2-(4-chloro-2-(trifluoromethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(70 mg, 0.128 mmol, 13% yield) as a white solid. MS (ESI) m/z 545.97(M+1)⁺. ¹H NMR (300 MHz, DMSO-d₆) δ (ppm) 10.95 (br s, 1H), 9.72 (br t,J=5.7 Hz, 1H), 7.79 (d, J=9.2 Hz, 1H), 7.71-7.61 (m, 3H), 7.46 (s, 1H),7.41 (d, J=8.1 Hz, 1H), 5.10 (br dd, J=5.1, 13.2 Hz, 1H), 4.50-4.25 (m,4H), 2.99-2.80 (m, 1H), 2.68-2.53 (m, 1H), 2.47-2.30 (m, 2H), 2.04-1.92(m, 1H).

Example 48N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-methoxyethoxy)phenyl)acetamide

A. 1-Iodo-3-(2-methoxyethoxy)benzene

To a stirred solution of 3-iodophenol (2 g, 9.09 mmol) inN,N-dimethylformamide (20 mL) was added potassium carbonate (3.13 g,22.72 mmol) followed by 1-bromo-2-methoxyethane (1.51 g, 10.90 mmol) atRT and stirred at 70° C. for 16 h. The reaction mixture was quenchedwith ice water (30 mL) and extracted with ethyl acetate (3×20 mL). Thecombined organic layers were washed with water (20 mL), brine (20 mL),dried over sodium sulfate, filtered and concentrated. Obtained crude waspurified by column chromatography (100-200 silica gel) using 15% ethylacetate in pet ether was used as eluent to afford1-iodo-3-(2-methoxyethoxy)benzene (1.3 g, 4.69 mmol, 52% yield) ascolorless liquid. MS (ESI) m/z 279.04 [M+1]⁺.

B. Ethyl 2,2-difluoro-2-(3-(2-methoxyethoxy)phenyl)acetate

To a stirred solution of 1-iodo-3-(2-methoxyethoxy)benzene (1 g, 3.6mmol) in dimethylsulfoxide (15 mL) was added ethyl2-bromo-2,2-difluoroacetate (0.69 mL, 5.41 mmol) and copper (0.59 g,9.36 mmol) at 0° C. and stirred at 60° C. for 5 h. The reaction mixturewas quenched with ice water and filtered through celite pad; filtratewas extracted with ethyl acetate (3×20 mL). The combined organic layerswere washed with water (15 mL), brine (15 mL), dried over sodiumsulfate, filtered and concentrated to afford ethyl2,2-difluoro-2-(3-(2-methoxyethoxy)phenyl)acetate (0.60 g, 2.19 mmol,61%) as a brown liquid. MS (ESI) m/z 274.1 [M]⁺.

C. 2,2-Difluoro-2-(3-(2-methoxyethoxy)phenyl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(3-(2-methoxyethoxy)phenyl)acetate (800 mg, 2.93 mmol) inmethanol:tetrahydrofuran:water mixture (15 mL, 1:1:1) was added lithiumhydroxide monohydrate (370 mg, 8.79 mmol) and stirred at roomtemperature for 5 h. The reaction mixture was concentrated and obtainedcrude was diluted with water (10 mL) and washed with ethyl acetate (2×10mL). Aqueous layer was acidified with 2N aqueous hydrochloric acid (10mL) and extracted with ethyl acetate (3×15 mL). The combined organiclayers were washed with brine (15 mL), dried over sodium sulfate,filtered; filtrate was concentrated to afford2,2-difluoro-2-(3-(2-methoxyethoxy)phenyl)acetic acid (600 mg, 3.47mmol, 83% yield) as a brown semi solid. ¹H NMR (300 MHz, DMSO-d₆) δ7.37-7.33 (m, 1H), 7.22-7.15 (m, 2H), 7.05-7.03 (m, 1H), 4.84 (brs, 1H),4.14 (s, 3H), 3.86-3.77 (m, 4H).

D.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-methoxyethoxy)phenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(3-(2-methoxyethoxy)phenyl)acetic acid (285 mg, 1.16mmol) in pyridine (3 mL) was added phosphoryl chloride (0.27 mL, 2.91mmol) dropwise and stirred at 0-5° C. for 1 h and then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) and stirred at room temperature for 30min. The reaction mixture was basified with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×15 mL). Thecombined organic layers were washed with water (15 mL), brine (15 mL),dried over sodium sulfate and filtered, concentrated. The resultantresidue was purified by Reveleris C-18 reversed phase columnchromatography using 50-55% acetonitrile in aqueous formic acid (0.1%)affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-methoxyethoxy)phenyl)acetamide(48 mg, 0.09 mmol, 9% yield) as an off-white solid. MS (ESI) m/z 501.96[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.54 (t, J=5.8 Hz,1H), 7.67 (d, J=8.1 Hz, 1H), 7.47-7.35 (m, 3H), 7.16-7.11 (m, 3H), 5.12(dd, J=13.2, 5.1 Hz, 1H), 4.45-4.27 (m, 4H), 4.11 (t, J=4.2 Hz, 2H),3.65 (t, J=4.5 Hz, 2H), 3.30 (s, 3H), 2.91-2.80 (m, 1H), 2.63-2.57 (m,1H), 2.44-2.36 (m, 1H), 2.08-2.05 (m, 1H).

Example 49N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-hydroxyethoxy)phenyl)acetamide

A. (2-Bromoethoxy)(tert-butyl)dimethylsilane

To a stirred solution of 2-bromoethanol (10 g, 80 mmol) indichloromethane (100 mL) was added tert-butylchlorodimethylsilane (14.5g, 96.77 mmol) and imidazole (10 g, 161.2 mmol) at 0° C. and stirred atroom temperature for 12 h. The reaction mixture was quenched withaqueous sodium bicarbonate solution (40 mL) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with water(40 mL), brine (40 mL), dried over sodium sulfate and concentrated toafford (2-bromoethoxy)(tert-butyl)dimethylsilane (8 g, 33.61 mmol, 42%yield) as colorless liquid.

B. Tert-butyl(2-(3-iodophenoxy)ethoxy)dimethylsilane

To a stirred solution of (2-bromoethoxy)(tert-butyl)dimethylsilane (5.19g, 21.8 mmol) in N,N-dimethylformamide (20 mL) was added potassiumcarbonate (6.27 g, 45.45 mmol), tetrabutyl ammonium iodide (1.34 g, 3.63mmol) followed by 3-iodophenol (4 g, 18.18 mmol) at RT and stirred at70° C. for 16 h. The reaction mixture was quenched with ice water (20mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with water (40 mL), brine (40 mL), dried over sodiumsulfate, filtered and concentrated. Obtained crude was purified bycolumn chromatography (100-200 silica gel, 15% ethyl acetate in petether) to afford tert-butyl(2-(3-iodophenoxy)ethoxy)dimethylsilane (3.5g, 9.25 mmol, 43% yield) as colorless liquid. ¹H NMR (300 MHz, CDCl₃) δ7.28-7.26 (m, 2H), 6.98 (t, J=8.4 Hz, 1H), 6.89-6.86 (m, 1H), 4.02-3.94(m, 4H), 0.90 (s, 9H), 0.07 (s, 6H).

C. Methyl 2,2-difluoro-2-(3-(2-hydroxyethoxy)phenyl)acetate

To a stirred solution oftert-butyl(2-(3-iodophenoxy)ethoxy)dimethylsilane (1 g, 2.64 mmol) indimethylsulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate(0.8 g, 3.97 mmol) and copper (0.43 g, 6.87 mmol) at 0° C. and stirredat 60° C. for 5 h. The reaction mixture was quenched with ice water andfiltered through a Celite pad. The filtrate was extracted with ethylacetate (3×20 mL) and the combined organic layers were washed with water(15 mL), brine (15 mL), dried over sodium sulfate, filtered andconcentrated to afford methyl2,2-difluoro-2-(3-(2-hydroxyethoxy)phenyl)acetate (0.2 g, 0.77 mmol,29%) as a brown liquid. MS (ESI) m/z 260.2 [M]⁺.

D. 2,2-Difluoro-2-(3-(2-hydroxyethoxy)phenyl)acetic acid

To an ice cold solution of methyl2,2-difluoro-2-(3-(2-hydroxyethoxy)phenyl)acetate (200 mg, 0.77 mmol) inmethanol:tetrahydrofuran:water mixture (15 mL, 1:1:1) was added lithiumhydroxide monohydrate (97 mg, 2.31 mmol) and stirred at room temperaturefor 5 h. The volatiles were removed under reduced pressure and resultantresidue was diluted with water (6 mL) and washed with ethyl acetate (2×5mL). Aqueous layer was acidified with 2N aqueous hydrochloric acid (5mL) and extracted with ethyl acetate (3×5 mL). The combined organiclayers were washed with brine (5 mL), dried over sodium sulfate,concentrated to afford 2,2-difluoro-2-(3-(2-hydroxyethoxy)phenyl)aceticacid (150 mg, 0.65 mmol, 84% yield) as a brown semi solid. ¹H NMR (300MHz, CDCl₃) δ 7.49-7.43 (m, 1H), 7.19-7.05 (m, 3H), 4.05-3.99 (m, 2H),3.85 (brs, 1H), 3.73-3.70 (m, 2H).

E.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-hydroxyethoxy)phenyl)acetamide

To an ice cold solution of3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) and2,2-difluoro-2-(3-(2-hydroxyethoxy)phenyl)acetic acid (225 mg, 0.97mmol) in N,N-dimethylformamide (10 mL) was addedN,N-diisopropylethylamine (0.52 mL, 2.91 mmol) followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (479 mg, 1.26 mmol) and stirred at roomtemperature for 4 h. The reaction mixture was diluted with ice water (15mL) and extracted with ethyl acetate (3×15 mL). The combined organiclayers were washed with brine (15 mL), dried over sodium sulfate,filtered, concentrated and obtained crude was purified by Reveleris C-18reversed phase column (50% acetonitrile in 0.1% aqueous formic acid) toaffordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-hydroxyethoxy)phenyl)acetamide (61 mg, 0.16 mmol, 16% yield) as an off-whitesolid. MS (ESI) m/z 488.08 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s,1H), 9.56 (s, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.47-7.35 (m, 3H), 7.15-7.12(m, 3H), 5.10 (dd, J=12.6, 4.5 Hz, 1H), 4.88 (t, J=5.7 Hz, 1H),4.45-4.27 (m, 4H), 4.11 (t, J=4.8 Hz, 2H), 3.71 (q, J=4.8 Hz, 2H),2.91-2.87 (m, 1H), 2.62-2.56 (m, 1H), 2.41-2.35 (m, 1H), 2.02-1.97 (m,1H).

Example 50N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(2-methoxyethoxy)phenyl)acetamide

A. 1-Iodo-4-(2-methoxyethoxy)benzene

To a stirred solution of 4-iodophenol (2 g, 9.09 mmol) inN,N-dimethylformamide (25 mL) was added 1-bromo-2-methoxyethane (1.5 g,10.90 mmol) tetrabutyl ammonium iodide (670 mg, 1.818 mmol) andpotassium carbonate (3.13 g, 22.72 mmol) at rt and stirred at 70° C. for16 h. The reaction mixture was quenched with ice cold water (40 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×10 mL), brine (10 mL), dried over sodium sulphateand concentrated to afford 1-iodo-4-(2-methoxyethoxy)benzene (600 mg,2.15 mmol, 24% yield) as colorless liquid. MS (ESI) m/z 277.9 [M+1]⁺.

B. Ethyl 2,2-Difluoro-2-(4-(2-methoxyethoxy)phenyl)acetate

To a stirred solution of 1-iodo-4-(2-methoxyethoxy)benzene (500 mg,1.798 mmol) in dimethylsulfoxide (5 mL) was reacted with ethyl2-bromo-2,2-difluoroacetate (0.34 mL, 2.69 mmol), copper (297 mg, 4.67mmol) and stirred for 12 h at 50° C. The reaction mixture wasneutralized with aqueous saturated ammonium chloride solution andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×10 mL), brine (10 mL), dried over sodium sulphateconcentrated to afford ethyl2,2-difluoro-2-(4-(2-methoxyethoxy)phenyl)acetate (120 mg, 0.437 mmol,24%) as a brown liquid. GCMS (m/z) 274 [M]+

C. 2,2-Difluoro-2-(4-(2-methoxyethoxy)phenyl)acetic acid

To a cold (0° C.) stirred solution of ethyl ethyl2,2-difluoro-2-(4-(2-methoxyethoxy)phenyl)acetate (1 g, 3.64 mmol) in inethanol/tetrahydrofuran/water mixture (15 mL, 1:1:1) was added lithiumhydroxide monohydrate (460 mg, 10.94 mmol) and stirred at roomtemperature for 12 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous hydrochloric acid (10 mL) andextracted with ethyl acetate (2×20 mL). The combined organic layer waswashed with brine (10 mL), dried over sodium sulphate and concentratedto afford 2,2-difluoro-2-(4-(2-methoxyethoxy)phenyl)acetic acid (600 mg,2.43 mmol, 66% yield) as a brown semi solid. Without furtherpurification crude compound used for next step.

D.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(2-hydroxyethoxy)phenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(4-(2-methoxyethoxy)phenyl)acetic acid (573 mg, 2.33mmol) in pyridine was added phosphorus oxychloride (0.54 mL, 5.82 mmol)dropwise and stirred at 0-5° C. for 1 h and then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (600 mg, 1.94 mmol) and stirred at room temperature for 30min. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layer was washed with water (2×20 mL), brine (20 mL)and dried over sodium sulphate and concentrated. The resultant residuewas purified by Reveleris C-18 reversed phase column chromatographyusing 40-55% acetonitrile in aqueous formic acid (0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(2-methoxyethoxy)phenyl)acetamide(40 mg, 0.079 mmol, 4% yield) as a white solid. MS (ESI) m/z 502.08[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆): δ 10.98 (s, 1H), 9.57 (br t, J=6.1Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.42-7.32 (m,2H), 7.07 (d, J=8.8 Hz, 2H), 5.10 (dd, J=13.2, 5.1 Hz, 1H), 4.44-4.25(m, 4H), 4.20-4.10 (m, 2H), 3.78-3.60 (m, 2H), 3.25 (s, 3H), 3.00-2.83(m, 1H), 2.66-2.56 (m, 1H), 2.45-2.32 (m, 1H), 2.05-1.94 (m, 1H).

Example 51N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-hydroxyethyl)phenyl)acetamide

A. 2-(3-Iodophenyl)ethanol

To a stirred solution of 2-(3-iodophenyl)acetic acid (1 g, 3.81 mmol) intetrahydrofuran (20 mL) was added borane dimethyl sulfide complex (1 mL,11.45 mmol) at 0° C. and stirred at room temperature for 16 h. Thereaction mixture was quenched with 4N hydrochloride acid (15 mL) andextracted with ethyl acetate (3×15 mL). The combined organic layers werewashed with water (15 mL), brine (15 mL), dried over sodium sulfate,filtered and concentrated to afford 2-(3-iodophenyl)ethanol (0.9 g, 3.63mmol, 95% yield) as colorless liquid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.61(s, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.08 (dd,J=7.8, 7.5 Hz, 1H), 3.59 (t, J=6.6 Hz, 2H), 2.67 (t, J=6.0 Hz, 2H).

B. 3-Iodophenethyl acetate

To a stirred solution of 2-(3-iodophenyl)ethanol (900 mg, 3.62 mmol) inpyridine (15 mL) was added acetic anhydride (1.11 g, 10.88 mmol) at 0°C. and stirred at 80° C. for 2 h. The reaction mixture was quenched with1N aqueous hydrochloride (10 mL) at room temperature and extracted withethyl acetate (3×15 mL). The combined organic layers were washed withwater (15 mL), brine (15 mL), dried over sodium sulfate and concentratedto afford 3-iodophenethyl acetate (700 mg, 2.41 mmol, 66% yield) ascolorless liquid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.66 (s, 1H), 7.59 (d,J=5.7 Hz, 1H), 7.28 (d, J=6.5 Hz, 1H), 7.11 (dd, J=8.0 Hz, 7.8 Hz, 1H),4.20 (t, J=6.8 Hz, 2H), 2.85 (t, J=6.8 Hz, 2H), 1.97 (s, 3H).

C. Ethyl 2-(3-(2-acetoxyethyl)phenyl)-2,2-difluoroacetate

To a stirred solution of 3-iodophenethyl acetate (1 g, 3.46 mmol) indimethyl sulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate(1.05 g, 5.19 mmol) followed by copper powder (0.57 g, 8.99 mmol) atroom temperature and stirred at 50° C. for 16 h. The reaction mixturewas neutralized with aqueous saturated ammonium chloride solution andextracted with ethyl acetate (3×15 mL). The combined organic layers werewashed with water (15 mL), brine (15 mL), dried over sodium sulfate andconcentrated to afford ethyl2-(3-(2-acetoxyethyl)phenyl)-2,2-difluoroacetate (550 mg, 1.92 mmol,55%) as a brown liquid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.49-7.46 (m, 2H),7.41-7.34 (m, 2H), 4.31-4.27 (m, 4H), 2.98 (t, J=7.2 Hz, 2H), 2.03 (s,3H), 1.31 (t, J=6.8 Hz, 3H).

D. 2,2-Difluoro-2-(3-(2-hydroxyethyl)phenyl)acetic acid

To an ice cold solution of ethyl2-(3-(2-acetoxyethyl)phenyl)-2,2-difluoroacetate (0.8 g, 2.77 mmol) inethanol/tetrahydrofuran/water mixture (15 mL, 1:1:1) was added lithiumhydroxide monohydrate (349 mg, 8.3 mmol) and stirred at room temperaturefor 16 h. The volatiles were removed and the residue was diluted withwater (10 mL), washed with ethyl acetate (2×10 mL). Aqueous layeracidified with 2N aqueous hydrochloric acid (10 mL) and extracted withethyl acetate (3×15 mL). The combined organic layers were washed withbrine (15 mL), dried over sodium sulfate, filtered and concentrated toafford 2,2-difluoro-2-(3-(2-hydroxy ethyl)phenyl)acetic acid (450 mg,2.08 mmol, 75% yield) as a brown semi solid. ¹H NMR (300 MHz, DMSO-d₆) δ7.56-7.39 (m, 4H), 3.62 (t, J=6.6 Hz, 2H), 2.78 (t, J=6.6 Hz, 2H), 1.91(s, 1H).

E.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-hydroxyethyl)phenyl)acetamide

To an ice cold solution of3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) and2,2-difluoro-2-(3-(2-hydroxyethyl)phenyl)acetic acid (209 mg, 0.97 mmol)in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine(0.52 mL, 2.91 mmol) followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (479 mg, 1.26 mmol) and stirred at roomtemperature for 16 h. The reaction mixture was diluted with water (15mL) and extracted with ethyl acetate (3×15 mL). The combined organiclayers were washed with brine (15 mL), dried over sodium sulphate,filtered and concentrated. The obtained crude product was purified byReveleris C-18 reversed phase column (50% acetonitrile in 0.1% aqueousformic acid to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-hydroxyethyl)phenyl)acetamide(50 mg, 0.10 mmol, 11% yield) as an off-white solid. MS (ESI) m/z 472.11[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.61 (t, J=6.3 Hz,1H), 7.67 (d, J=8.1 Hz, 1H), 7.43-7.41 (m, 5H), 7.36 (d, J=8.1 Hz, 1H),6.67 (t, J=5.1 Hz, 1H), 5.10 (dd, J=13.8, 5.1 Hz, 1H), 4.45 (d, J=6.0Hz, 2H), 4.43 (t, J=15.3 Hz, 1H), 4.28 (d, J=17.7 Hz, 1H), 3.61 (q,J=5.1 Hz, 2H), 2.96-2.83 (m, 1H), 2.75 (t, J=6.9 Hz, 2H), 2.67-2.54 (m,1H), 2.46-2.30 (m, 1H), 2.04-1.92 (m, 1H).

Example 522-(3-(Dimethylamino)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. 3-Iodo-N,N-dimethylaniline

To a stirred solution of 3-iodoaniline (300 mg, 1.36 mmol) in ethanol(10 mL) was added formaldehyde (82 mg, 2.73 mmol), molecular sieves (1g) and acetic acid (2 mL) at 0° C., stirred at room temperature for 8 h.The reaction mixture was cooled at 0° C. and treated with sodium cyanoborohydride (200 g, 2.73 mmol) and stirred at room temperature for 16 h.The reaction mixture was filtered through a Celite pad and the filtratewas diluted with water (10 mL) and basified with aqueous sodiumbicarbonate solution and extracted with ethyl acetate (3×10 mL).Combined organic layers were washed with water (10 mL) and brine (10mL), dried over sodium sulfate, filtered and concentrated under reducedpressure to give crude compound. Obtained crude was purified by silicagel column chromatography (30% ethyl acetate in pet ether) to afford3-iodo-N,N-dimethylaniline (210 mg, 0.85 mmol, 74% yield) as a liquid.¹H NMR (300 MHz, CDCl₃) δ 7.03-6.89 (m, 3H), 6.67-6.64 (m, 1H), 2.92 (s,6H).

B. Ethyl 2-(3-(dimethylamino)phenyl)-2,2-difluoroacetate

To a stirred solution of 3-iodo-N,N-dimethylaniline (250 mg, 1.01 mmol)in dimethylsulfoxide (10 mL) was added ethyl 2-bromo-2,2-difluoroacetate(0.19 mL, 1.52 mmol) followed by copper powder (167 mg, 2.63 mmol) at RTand stirred at 55° C. for 5 h. The reaction mixture was diluted withwater and filtered through a Celite pad. The filtrate was basified withaqueous saturated sodium bicarbonate solution and extracted with ethylacetate (3×10 mL). The combined organic layers were washed with water(10 mL), brine (10 mL), dried over sodium sulfate, filtered,concentrated to afford ethyl2-(3-(dimethylamino)phenyl)-2,2-difluoroacetate (80 mg, 6.99 mmol, 33%)as a brown liquid. MS (ESI) m/z 243.2 [M]⁺

C. 2-(3-(Dimethylamino)phenyl)-2,2-difluoroacetic acid

To an ice cold solution of ethyl2-(3-(dimethylamino)phenyl)-2,2-difluoroacetate (500 mg, 2.06 mmol) inin methanol/tetrahydrofuran/water mixture (15 mL, 1:1:1) was addedlithium hydroxide monohydrate (260 mg, 6.17 mmol) and stirred at roomtemperature for 4 h. The reaction mixture was concentrated and theresultant residue was diluted with water (10 mL) and washed with ethylacetate (2×10 mL). Aqueous layer acidified with aqueous potassiumbisulfate (10 mL) and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were washed with brine (10 mL), dried oversodium sulfate, filtered and concentrated to afford2-(3-(dimethylamino)phenyl)-2,2-difluoroacetic acid (400 mg, 1.86 mmol,91% yield) as a brown semi solid ¹H NMR (300 MHz, DMSO-d₆) δ 7.64-7.55(m, 3H), 7.38-7.32 (m, 1H), 2.56 (s, 6H).

D.2-(3-(Dimethylamino)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To an ice cold solution of3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) and2-(3-(dimethylamino)phenyl)-2,2-difluoroacetic acid (208 mg, 0.97 mmol)in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine(0.52 mL, 2.91 mmol) followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (479 mg, 1.26 mmol) and stirred at roomtemperature for 16 h. The reaction mixture was diluted with water (15mL) and extracted with ethyl acetate (3×15 mL). The combined organiclayers were washed with brine (15 mL), dried over sodium sulfate,filtered and concentrated. The obtained crude was purified by RevelerisC-18 reversed phase column (50% acetonitrile in 0.1% aqueous formicacid) to afford2-(3-(dimethylamino)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(63 mg, 0.13 mmol, 13% yield) as an off-white solid. MS (ESI) m/z 470.8[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.21 (t, J=5.8 Hz,1H), 7.72 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.57-7.48 (m, 4H),7.32 (dd, J=8.4, 6.9 Hz, 1H), 5.11 (dd, J=13.2, 4.8 Hz, 1H), 4.48 (d,J=6.6 Hz, 2H), 4.46 (d, J=16.5 Hz, 1H), 4.32 (d, J=17.4 Hz, 1H),2.98-2.86 (m, 1H), 2.73-2.57 (m, 1H), 2.51-2.33 (m, 1H), 2.34 (s, 6H),2.07-1.98 (m, 1H).

Example 53N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(piperidin-1-yl)phenyl)acetamide

A. 1-(3-Iodophenyl)piperidine

To a stirred solution of 3-iodoaniline (5 g, 22.83 mmol) in toluene (50mL) was added N,N-diisopropylethylamine (20 mL, 114.1 mmol) followed by1,5-dibromopentane (4.06 mL, 29.68 mmol) at 0° C. and stirred at 100° C.for 16 h. The reaction mixture was basified aqueous saturated sodiumbicarbonate solution and extracted with ethyl acetate (3×40 mL). Thecombined organic layers were washed with water (40 mL), brine (40 mL),dried over sodium sulfate, filtered; filtrate and concentrated. Theobtained crude was purified by flash column chromatography (25% ethylacetate in pet ether) to afford 1-(3-iodophenyl)piperidine (2.8 g, 9.75mmol, 43% yield) as a colorless liquid. MS (ESI) m/z 287.90 [M+1]⁺.

B. Ethyl 2,2-difluoro-2-(3-(piperidin-1-yl)phenyl)acetate

To a stirred solution of 1-(3-iodophenyl)piperidine (500 mg, 1.74 mmol)in dimethyl sulfoxide (5 mL) was added ethyl 2-bromo-2,2-difluoroacetate(690 mg, 2.61 mmol) followed by copper powder (290 mg, 4.53 mmol) atroom temperature and stirred at 55° C. for 16 h. The reaction mixturewas diluted with water and filtered through a Celite pad. The filtratewas extracted with ethyl acetate (3×10 mL) and the combined organiclayers were washed with water (10 mL), brine (10 mL), dried over sodiumsulfate, filtered and concentrated. The resultant crude product waspurified by flash column chromatography (25% ethyl acetate in pet ether)to afford ethyl 2,2-difluoro-2-(3-(piperidin-1-yl)phenyl)acetate (200mg, 0.71 mmol, 41% yield) as a colorless liquid. MS (ESI) m/z 283.2[M]⁺.

C. 2,2-Difluoro-2-(3-(piperidin-1-yl)phenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(3-(piperidin-1-yl)phenyl)acetate (250 mg, 0.88 mmol) inmixture of tetrahydrofuran:methanol:water (5 mL, 1:1:1) was addedlithium hydroxide monohydrate (110 mg, 2.65 mmol) and stirred at roomtemperature for 16 h. The reaction mixture was concentrated underreduced pressure and the obtained residue was dissolved in water (10 mL)and washed with ethyl acetate (2×10 mL). Aqueous layer was acidifiedwith aqueous potassium bisulfate and extracted with ethyl acetate (3×10mL). The combined organic layers were washed with brine (10 mL), driedover sodium sulfate, filtered and concentrated to afford2,2-difluoro-2-(3-(piperidin-1-yl)phenyl)acetic acid (200 mg, 0.78 mmol,88% yield) as semi-solid compound. ¹H NMR (300 MHz, CDCl₃) δ 8.27 (d,J=9.3 Hz, 1H), 7.89 (s, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.49 (dd, J=7.8 Hz,7.6 Hz, 1H), 4.28 (brs, 1H), 3.49-3.39 (m, 4H), 2.12-2.08 (m, 4H),1.69-1.65 (m, 2H).

D.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(piperidin-1-yl)phenyl)acetamide

To an ice cold solution of2,2-difluoro-2-(3-(piperidin-1-yl)phenyl)acetic acid (206 mg, 0.81 mmol)in pyridine (6 mL) was added phosphorus oxychloride (371 mg, 2.43 mmol)drop wise and stirred at 0-5° C. for 1 h. Then,3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (250 mg, 0.81 mmol) was added into the reaction mixtureand stirred at room temperature for 2 h. The reaction mixture wasbasified with aqueous saturated sodium bicarbonate and extracted withethyl acetate (3×15 mL). The combined organic layers were washed withwater (15 mL), brine (15 mL), dried over sodium sulfate, filtered andconcentrated. The resultant residue was purified by Reveleris C-18reversed phase column chromatography (50-55% acetonitrile in 0.1%aqueous formic acid to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(piperidin-1-yl)phenyl)acetamide(62 mg, 0.12 mmol, 15% yield) as white solid. MS (ESI) m/z 510.81[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.57 (t, J=5.7 Hz,1H), 7.66 (d, J=7.5 Hz, 1H), 7.39 (s, 1H), 7.35 (d, J=5.1 Hz, 1H), 7.30(d, J=8.1 Hz, 1H), 7.08 (d, J=8.7 Hz, 1H), 7.00 (s, 1H), 6.92 (d, J=7.5Hz, 1H), 5.10 (dd, J=13.2, 4.8 Hz, 1H), 4.45 (d, J=6.0 Hz, 2H), 4.41 (d,J=17.7 Hz, 1H), 4.27 (d, J=17.4 Hz, 1H), 3.31-3.11 (m, 4H), 2.98-2.86(m, 1H), 2.63-2.57 (m, 1H), 2.40-2.27 (m, 2H), 2.01-1.97 (m, 1H),1.57-1.54 (m, 5H).

Example 54N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-morpholinophenyl)acetamide

A. 2,2′-Oxybis(ethane-2,1-diyl) dimethanesulfonate

To a stirred solution of 2,2′-oxydiethanol (2.0 g, 18.86 mmol) indichloromethane (20 mL) was added methane sulfonylchloride (2.1 g, 47.16mmol), triethylamine (13 mL, 94.33 mmol) at 0° C. and stirred at roomtemperature for 2 h. The reaction mixture was quenched with water (100mL) and extracted with dichloromethane (2×100 mL). The combined organiclayers were washed with brine (50 mL), dried over sodium sulphate andconcentrated to afford 2,2′-oxybis(ethane-2,1-diyl) dimethanesulfonate(4.0 g, 15.26 mmol, 81% yield). GC MS (m/z) 263.1.

B. 4-(3-Iodophenyl)morpholine

To a stirred solution of 3-iodo aniline (1.0 g, 4.56 mmol) in toluene(20 mL) was added 2,2′-Oxybis(ethane-2,1-diyl) dimethanesulfonate (2.1g, 9.13 mmol), diisopropylethylamine (4 mL, 22.82 mmol) and stirredunder reflux for 16 h. The reaction mixture was quenched with water (100mL) and extracted with ethyl acetate (2×100 mL). The combined organiclayers were washed with brine (50 mL), dried over sodium sulphate andconcentrated to give 4-(3-iodophenyl)morpholine (1.2 g, 4.15 mmol, 91%yield). LCMS (ESI) m/z 290.16[M+1]⁺.

C. Ethyl 2,2-difluoro-2-(3-morpholinophenyl)acetate

To a stirred solution of 4-(3-iodophenyl)morpholine (1.2 g, 4.15 mmol)in dimethylsulfoxide (50 mL) was added ethyl 2-bromo-2,2-difluoroacetate(0.6 mL, 4.98 mmol), copper (686 mg, 10.79 mmol) and stirred for 6 h at55° C. The reaction mixture was neutralized with aqueous saturatedammonium chloride solution and extracted with ethyl acetate (3×100 mL).The combined organic layers were washed with water (2×50 mL), brine (50mL), dried over sodium sulphate and concentrated to afford ethyl2,2-difluoro-2-(3-morpholinophenyl)acetate (700 mg, 2.45 mmol, 59%yield). GC MS (m/z) 285.2.

D. 2,2-Difluoro-2-(3-morpholinophenyl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(3-morpholinophenyl)acetate (700 mg, 2.45 mmol) intetrahydrofuran-methanol-water (20 mL, 1:1:1) was added lithiumhydroxide monohydrate (309 mg, 7.36 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous potassium bisulphate (5 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine (20 mL), dried over sodium sulphate and concentratedto afford 2,2-difluoro-2-(3-morpholinophenyl)acetic acid (550 mg, 2.14mmol, 87% yield). LCMS (ESI) m/z 258.12[M+1]⁺.

E.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-morpholinophenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(3-morpholinophenyl)acetic acid (300 mg, 1.16 mmol) inpyridine (5 mL) was added phosphoryl chloride (0.4 mL, 3.50 mmol) andstirred at 0-5° C. for 1 h. To this reaction mixture was added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (361 mg, 1.16 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (2×25 mL). Thecombined organic layers were washed with water (15 mL), brine (15 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase column chromatography using40-45% acetonitrile in aqueous formic acid (0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-morpholinophenyl)acetamide (80 mg, 0.15 mmol, 13% yield) as an off white solid. LCMS(ESI) m/z 512.95 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ=10.98 (s, 1H), 9.58(br t, J=6.1 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.52-7.31 (m, 2H), 7.11(br d, J=8.3 Hz, 1H), 7.07-6.95 (m, 1H), 5.10 (dd, J=4.9, 13.2 Hz, 1H),4.51-4.26 (m, 4H), 3.77-3.66 (m, 4H), 3.14-3.03 (m, 4H), 2.98-2.84 (m,1H), 2.66-2.55 (m, 1H), 2.45-2.30 (m, 1H), 2.06-1.94 (m, 1H)

Example 55N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-isopropoxyphenyl)acetamide

A. 1-(4-Fluoro-2-isopropoxycyclohexyl)ethanone

To a stirred solution of 1-(4-fluoro-2-hydroxyphenyl)ethanone (3 g,19.48 mmol) in N,N-dimethylformamide (15 mL) was added 2-bromopropane(5.94 g, 48.76 mmol) potassium carbonate (8.06 g 58.44 mmol) and stirredfor 16 h at 90° C. The reaction mixture was diluted with ethyl acetate(30 mL) and extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with water (2×50 mL), brine (50 mL) and driedover sodium sulphate and was concentrated to afford1-(4-fluoro-2-isopropoxyphenyl)ethanone (2.5 g, 12.75 mmol, 65% yield)as a brown liquid. MS (ESI) m/z 197.33 [M]⁺

B. Ethyl 2-(4-fluoro-2-isopropoxyphenyl)-2-oxoacetate

To a stirred solution of 1-(4-fluoro-2-isopropoxyphenyl)ethanone (2.0 g,10.20 mmol) in pyridine (15 mL) was added selenium dioxide (2.83 g,25.51 mmol) and stirred for 16 h at 100° C. The reaction mixture wasdiluted with dichloromethane (30 mL) and filtered through Celite pad.The filtrate was treated with ethyl chloroformate (6 mL) at 0° C. andstirred at room temperature for 3 h. The reaction mixture wasneutralized with 1N aqueous hydrochloric acid (up to pH-4) and extractedwith ethyl acetate (2×100 mL). The combined organic layers were washedwith water (2×50 mL), brine (50 mL) and dried over sodium sulphate andconcentrated. The crude was purified with column chromatography using100-200 mesh silica gel eluting 10% ethylacetate in hexanes to affordethyl 2-(4-fluoro-2-isopropoxyphenyl)-2-oxoacetate (800 g, 3.14 mmol,32% yield) as a brown liquid. MS (ESI) m/z 255.33 [M]⁺

C. Ethyl 2,2-difluoro-2-(4-fluoro-2-isopropoxyphenyl)acetate

To a stirred solution of ethyl2-(4-fluoro-2-isopropoxyphenyl)-2-oxoacetate (450 mg, 1.77 mmol) wasadded diethyl amino sulfur trifluoride (714 mg, 4.42 mmol) and stirredat room temperature for 16 h. The reaction mixture was basified withaqueous saturated sodium bicarbonate to pH-8 and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with water(2×30 mL), brine (30 mL), dried over sodium sulphate and concentrated toafford ethyl 2,2-difluoro-2-(4-fluoro-2-isopropoxyphenyl)acetate (200mg, 0.724 mmol, 40% yield) as a brown liquid. GC-MS (ESI) m/z 276 [M]⁺

D. 2,2-Difluoro-2-(4-fluoro-2-isopropoxyphenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(4-fluoro-2-isopropoxyphenyl)acetate (350 mg, 1.26 mmol)in tetrahydrofuran/Methanol/Water mixture (30 mL, 1:1:1) was addedlithium hydroxide monohydrate (160 mg, 3.80 mmol) and stirred at roomtemperature for 4 h. The reaction mixture was concentrated; the residueobtained was neutralized with 10% aqueous hydrochloric acid (10 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine (20 mL), dried over sodium sulphate and concentratedto afford 2,2-difluoro-2-(4-fluoro-2-isopropoxyphenyl)acetic acid (200mg, 0.806 mmol, 63% yield) as a brown semi solid. GC-MS (ESI) m/z 224.0[M]⁺; ¹H NMR (300 MHz, CDCl₃) δ ppm 7.62 (dd, J=8.4, 2.1 Hz, 1H), 7.19(brs, 1H), 6.72 (ddd, J=10.8, 8.4, 2.1 Hz, 1H), 6.65 (brd, J=10.5 Hz,1H), 4.58 (sep, J=5.7 Hz, 1H), 1.33 (d, J=6.3 Hz, 6H).

E.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-isopropoxyphenyl)acetamide

To an ice cold solution of2,2-difluoro-2-(4-fluoro-2-isopropoxyphenyl)acetic acid (289 mg, 1.165mmol) in pyridine (10 mL) was added POCl₃ (446 mg, 2.91 mmol) andstirring at 0-5° C. for 1 h. The reaction mixture was then treated with3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.970 mmol) and stirred at 0-30° C. for 1 h. Thereaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×10 mL), brine (10 mL),dried over sodium sulphate and concentrated. The crude product waspurified by Reveleris C-18 reversed phase column (45-55% acetonitrile in0.1% aqueous formic acid) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-isopropoxyphenyl)acetamide(35 mg, 0.069 mmol, 7% yield) as an off white solid. MS (ESI) m/z 503.95[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.98 (s, 1H), 9.32 (t, J=5.7Hz, 1H), 7.70 (d, J=7.70 Hz, 1H), 7.60-7.50 (m, 2H), 7.46 (br d, J=7.7Hz, 1H), 7.08 (br d, J=11.0 Hz, 1H), 6.85 (dd, J=8.7, 6.3 Hz, 1H), 5.11(dd, J=13.6, 4.77 Hz, 1H), 4.68 (sep, J=6.3 Hz, 1H), 4.53-4.23 (m, 3H),3.00-2.81 (m, 1H), 2.68-2.49 (m, 1H), 2.44-2.30 (m, 1H), 2.07-1.93 (m,1H), 1.11 (dd, J=4.5 Hz, 0.2 Hz, 6H).

Example 56N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2,2,2-trifluoroethoxy)phenyl)acetamide

A. 1-Iodo-2-(2,2,2-trifluoroethoxy)benzene

To a stirred solution of 2-iodophenol (2 g, 9.09 mmol) inN,N-dimethylformamide (30 mL) was added 1,1,1-trifluoro-2-iodoethane(1.34 mL, 13.63 mmol), followed by potassium carbonate (3.76 g 2.72mmol) and stirred at 50° C. for 16 h. The reaction mixture was dilutedwith ice water (40 mL) and extracted with ethyl acetate (3×40 mL). Thecombined organic layers were washed with water (40 mL), brine (40 mL),dried over sodium sulfate, filtered and concentrated to afford1-iodo-2-(2,2,2-trifluoroethoxy)benzene (1.6 g, 5.46 mmol, 58% yield) asa colorless liquid. MS (ESI) m/z 302.0 [M]⁺.

B. Ethyl 2,2-difluoro-2-(2-(2,2,2-trifluoroethoxy)phenyl)acetate

To a stirred solution of 1-iodo-2-(2,2,2-trifluoroethoxy)benzene (1.5 g,5.63 mmol) in dimethylsulfoxide (20 mL) was added ethyl2-bromo-2,2-difluoroacetate (1.1 mL, 8.44 mmol) followed by copper (0.92g, 14.63 mmol) at RT and stirred at 55° C. for 6 h. The reaction mixturewas basified with aqueous saturated sodium bicarbonate solution andextracted with ethyl acetate (3×20 mL). The combined organic layers werewashed with water (20 mL), brine (20 mL), dried over sodium sulfate,filtered and concentrated. The obtained crude was purified by silica gelcolumn chromatography (20% ethyl acetate in pet ether) to afford ethyl2,2-difluoro-2-(2-(2,2,2-trifluoroethoxy)phenyl)acetate (410 mg, 1.37mmol, 24%) as a colorless liquid. MS (ESI) m/z 298.1 [M]⁺.

C. 2,2-Difluoro-2-(2-(2,2,2-trifluoroethoxy)phenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(2-(2,2,2-trifluoroethoxy)phenyl)acetate (400 mg, 1.34mmol) in tetrahydrofuran:methanol:water (15 mL, 1:1:1) was added lithiumhydroxide monohydrate (169 mg, 4.02 mmol) and stirred at roomtemperature for 4 h. The volatiles were removed under reduced pressureand obtained crude was dissolved in water (15 mL) and washed with ethylacetate (2×10 mL). Aqueous layer was acidified with 1N hydrochlorideaqueous solution and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were washed with brine (15 mL), dried oversodium sulfate, filtered and solvent was concentrated to afford2,2-difluoro-2-(2-(2,2,2-trifluoroethoxy)phenyl)acetic acid (270 mg, 1mmol, 59% yield) as semi-solid compound. ¹H NMR (400 MHz, CDCl₃) δ 7.72(d, J=6.3 Hz, 1H), 7.51 (t, J=8.4 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 6.93(d, J=8.4 Hz, 1H), 6.68 (brs, 1H), 4.38 (q, J=8.1 Hz, 1H).

D.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2,2,2-trifluoroethoxy)phenyl)acetamide

To an ice cold solution of2,2′-difluoro-2-(2-(2,2,2-trifluoroethoxy)phenyl)acetic acid (262 mg,1.16 mmol) in pyridine (6 mL) was added phosphorus oxychloride (0.27 mL,2.9 mmol) drop wise and stirred at 0-5° C. for 1 h and then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) and stirred at room temperature for 2h. The reaction mixture was basified with aqueous saturated sodiumbicarbonate solution and extracted with ethyl acetate (3×15 mL). Thecombined organic layers were washed with water (15 mL), brine (15 mL),dried over sodium sulfate, filtered and concentrated. The resultantresidue was purified by Reveleris C-18 reversed phase columnchromatography (50-55% acetonitrile in 0.1% aqueous formic acid) toaffordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2,2,2-trifluoroethoxy)phenyl)acetamide(60 mg, 0.11 mmol, 11% yield) as white solid. MS (ESI) m/z 525.89[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.42 (t, J=5.4 Hz,1H), 7.70 (d, J=7.5 Hz, 1H), 7.63-7.52 (m, 2H), 7.49 (s, 1H), 7.43 (d,J=8.1 Hz, 1H), 7.26 (d, J=8.1 Hz, 1H), 7.18 (dd, J=7.7, 7.6 Hz, 1H),5.11 (dd, J=13.2, 4.8 Hz, 1H), 4.75 (q, J=8.7 Hz, 2H), 4.46 (d, J=17.1Hz, 1H), 4.45 (d, J=6.0 Hz, 2H), 4.31 (d, J=17.4 Hz, 1H), 2.92-2.86 (m,1H), 2.63-2.57 (m, 1H), 2.42-2.37 (m, 1H), 2.02-1.98 (m, 1H).

Example 57N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-4-fluorophenyl)-2,2-difluoroacetamide

A. 1-(2-Ethoxy-4-fluorophenyl)ethanone

To a stirred solution of 1-(4-fluoro-2-hydroxyphenyl)ethanone (3 g,19.48 mmol) in N,N-dimethylformamide (15 mL) was added bromoethane (5.30g, 48.76 mmol) potassium carbonate (8.06 g 58.44 mmol) and stirred for16 h at 100° C. The reaction mixture was diluted with ethylacetate (30mL) and extracted with ethyl acetate (2×100 mL). The combined organiclayers were washed with water (2×50 mL), brine (50 mL), dried oversodium sulphate and concentrated to afford1-(2-ethoxy-4-fluorophenyl)ethanone (2.6 g, 14.28 mmol, 74% yield) as abrown liquid. MS (ESI) m/z 183.17 [M]⁺

B. Ethyl 2-(2-ethoxy-4-fluorophenyl)-2-oxoacetate

To a stirred solution of 1-(2-ethoxy-4-fluorophenyl)ethanone (1.0 g,5.49 mmol) in pyridine (15 mL) was added selenium dioxide (1.52 g, 13.73mmol) and stirred for 16 h at 100° C. The reaction mixture was dilutedwith dichloromethane (30 mL) and filtered through Celite pad. To thefiltrate was added ethyl chloroformate (3 mL) at 0° C. and stirred atroom temperature for 3 h. The reaction mixture was neutralized with 1Naqueous hydrochloric acid (up to pH-4) and extracted with ethyl acetate(2×100 mL). The combined organic layers were washed with water (2×50mL), brine (50 mL), dried over sodium sulphate and concentrated. Thecrude was purified with column chromatography using 100-200 mesh silicagel eluting 10% ethylacetate-pet ether to afford ethyl2-(2-ethoxy-4-fluorophenyl)-2-oxoacetate (880 g, 3.66 mmol, 67% yield)as a brown liquid. MS (ESI) m/z 241.14 [M]⁺

C. Ethyl 2-(2-ethoxy-4-fluorophenyl)-2,2-difluoroacetate

To a stirred solution of ethyl 2-(2-ethoxy-4-fluorophenyl)-2-oxoacetate(800 mg, 3.33 mmol) was added diethyl amino sulfur trifluoride (1.34 g,8.33 mmol) and stirred for 16 h at room temperature. The reactionmixture was neutralized with aqueous saturated sodium bicarbonate (up topH-8) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with water (2×30 mL), brine (30 mL), dried oversodium sulphate and concentrated to afford ethyl2-(2-ethoxy-4-fluorophenyl)-2,2-difluoroacetate (450 mg, 1.71 mmol, 51%yield) as a brown liquid. GC-MS (ESI) m/z 262 [M]⁺

D. 2-(2-Ethoxy-4-fluorophenyl)-2,2-difluoroacetic acid

To a stirred solution of ethyl2-(2-ethoxy-4-fluorophenyl)-2,2-difluoroacetate (1 g, 3.81 mmol) intetrahydrofuran/Methanol/Water mixture (30 mL, 1:1:1) was added lithiumhydroxide monohydrate (480 mg, 11.45 mmol) and stirred at roomtemperature for 4 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous hydrochloric acid (10 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine (20 mL), dried over sodium sulphate and concentratedto afford 2-(2-ethoxy-4-fluorophenyl)-2,2-difluoroacetic acid (600 mg,2.56 mmol, 67% yield) as a brown semi solid. The crude compound used fornext step without further purification.

E.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-4-fluorophenyl)-2,2-difluoroacetamide

To a cold (0° C.) stirred solution of2-(2-ethoxy-4-fluorophenyl)-2,2-difluoroacetic acid (181 mg, 0.776 mmol)in pyridine (10 mL) was added phosphoryl chloride (294 mg, 1.93 mmol)and stirred at 0° C.-5° C. for 1 h. To this reaction mixture was thenadded 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (200 mg, 0.647 mmol) at 0° C. and allowed to warm roomtemperature stirring over a period of 1 h. The reaction mixture wasneutralized with saturated aqueous sodium bicarbonate (up to pH-8) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×10 mL), brine (10 mL), dried over sodium sulphateand concentrated. The crude product was purified by Reveleris C-18reversed phase column using 45-55% acetonitrile in aqueous formic acid(0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-4-fluorophenyl)-2,2-difluoroacetamide(80 mg, 0.163 mmol, 25% yield) as an off white solid. MS (ESI) m/z489.95 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.35 (br t,J=5.8 Hz, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.59 (dd, J=8.6, 6.8 Hz, 1H),7.50 (s, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.05 (br d, J=11.0 Hz, 1H), 6.88(td, J=8.5, 2.4 Hz, 1H), 5.11 (dd, J=13.3, 5.3 Hz, 1H), 4.50-4.26 (m,4H), 4.00 (q, J=6.9 Hz, 2H), 3.00-2.85 (m, 1H), 2.67-2.55 (m, 1H),2.44-2.31 (m, 1H), 2.06-1.95 (m, 1H), 1.11 (t, J=6.9 Hz, 3H).

Example 58N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-isopropoxyphenyl)acetamide

A. 1-Iodo-2-isopropoxybenzene

To a stirred solution of 2-iodophenol (2 g, 9.09 mmol) inN,N-dimethylformamide (20 mL) was added 2-bromopropane (3.38 mL, 36.3mmol) followed by potassium carbonate (3.76 g, 27.27 mmol) and stirredat 90° C. for 16 h. The reaction mixture was diluted with ice water (25mL) and extracted with ethyl acetate (3×20 mL). The combined organiclayers were washed with water (20 mL), brine (20 mL), dried over sodiumsulfate, filtered and concentrated to afford 1-iodo-2-isopropoxybenzene(2.0 g, 7.63 mmol, 84% yield) as a colorless liquid. MS (ESI) m/z 262.21[M]⁺.

B. Ethyl 2,2-difluoro-2-(2-isopropoxyphenyl)acetate

To a stirred solution of 1-iodo-2-isopropoxybenzene (2 g, 7.6 mmol) indimethylsulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate(1.5 mL, 11.45 mmol) followed by copper (1.26 g, 19.84 mmol) at RT andstirred at 55° C. for 6 h. The reaction mixture was basified withaqueous saturated sodium bicarbonate solution and extracted with ethylacetate (3×20 mL). The combined organic layers were washed with water(20 mL), brine (20 mL), dried over sodium sulfate, filtered andconcentrated. The obtained crude product was purified by flashchromatography (20% ethyl acetate in pet ether) to afford ethyl2,2-difluoror-2-(2-isopropoxyphenyl)acetate (1.3 g, 5.03 mmol, 66%) as acolorless liquid. MS (ESI) m/z 259.23 [M+1]⁺.

C. 2,2-Difluoro-2-(2-isopropoxyphenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(2-isopropoxyphenyl)acetate (1 g, 3.87 mmol) intetrahydrofuran:methanol:water (15 mL, 1:1:1) was added lithiumhydroxide monohydrate (0.49 g, 11.62 mmol) and stirred at roomtemperature for 4 h. The volatiles were removed under reduced pressureand obtained crude was dissolved in water (15 mL), washed with ethylacetate (2×10 mL). Aqueous layer was acidified with 1N hydrochlorideaqueous solution and extracted with ethyl acetate (3×15 mL). Thecombined organic layers were washed with brine (15 mL), dried oversodium sulfate, filtered and concentrated to afford2,2-difluoro-2-(2-isopropoxyphenyl)acetic acid (600 mg, 2.60 mmol, 67%yield) as semi-solid compound. ¹H NMR (300 MHz, CDCl₃) δ 8.75 (brs, 1H),7.65 (d, J=7.2 Hz, 1H), 7.44 (dd, J=8.0, 7.6 Hz, 1H), 7.03 (dd, J=8.0,7.2 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 4.66 (Sep, J=6.0 Hz, 1H), 1.32 (d,J=6.0 Hz, 6H).

D.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-isopropoxyphenyl)acetamide

To an ice cold solution of 2,2-difluoro-2-(2-isopropoxyphenyl)aceticacid (267 mg, 1.16 mmol) in pyridine (6 mL) was added phosphorusoxychloride (0.27 mL, 2.9 mmol) in drop wise and stirred at 0-5° C. for1 h. Then, 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) was added and stirred at roomtemperature for 2 h. The reaction mixture was basified with aqueoussaturated sodium bicarbonate solution and extracted with ethyl acetate(3×15 mL). The combined organic layers were washed with water (15 mL),brine (15 mL), dried over sodium sulfate, filtered and concentrated. Theresultant residue was purified by Reveleris C-18 reversed phase columnchromatography (50-55% acetonitrile in 0.1% aqueous formic acid) toaffordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-isopropoxyphenyl)acetamide(40 mg, 0.08 mmol, 8% yield) as white solid. MS (ESI) m/z 485.98 [M+1]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.26 (t, J=5.8 Hz, 1H), 7.70(d, J=7.8 Hz, 1H), 7.55-7.45 (m, 4H), 7.12 (d, J=8.4 Hz, 1H), 7.02 (dd,J=7.2, 7.0 Hz, 1H), 5.11 (dd, J=13.2, 5.1 Hz, 1H), 4.46 (Sep, J=6.0 Hz,1H), 4.45 (d, J=6.3 Hz, 2H), 4.44 (d, J=17.2, 1H), 4.31 (d, J=17.4 Hz,1H), 2.98-2.86 (m, 1H), 2.57-2.49 (m, 1H), 2.43-2.30 (m, 1H), 2.04-1.94(m, 1H), 1.13 (d, J=6.0 Hz, 3H), 1.12 (d, J=6.0 Hz, 3H).

Example 59N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-fluoro-4-isopropoxyphenyl)acetamide

A. 1-(2-Fluoro-4-isopropoxyphenyl)ethanone

To a stirred solution of 1-(2-fluoro-4-hydroxyphenyl)ethanone (300 mg,1.95 mmol) in N,N-dimethylformamide (3 mL) was added isopropyl iodide(397 mg, 2.33 mmol) followed by potassium carbonate (672 mg, 4.87 mmol)and stirred at 90° C. for 16 h. The reaction mixture was diluted withice water (20 mL) and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were washed with water (10 mL), brine (10 mL),dried over sodium sulfate, filtered and concentrated to afford1-(2-fluoro-4-isopropoxyphenyl)ethanone (300 mg, 1.53 mmol, 79% yield)as a colorless liquid. MS (ESI) m/z 197.2 [M+1]⁺.

B. Ethyl 2-(2-fluoro-4-isopropoxyphenyl)-2-oxoacetate

To a stirred solution of 1-(2-fluoro-4-isopropoxyphenyl)ethanone (300mg, 1.63 mmol) in pyridine (3 mL) was added selenium dioxide (452 mg,3.38 mmol) at room temperature. The reaction mixture was stirred at 100°C. for 16 h. The reaction mixture was filtered through a Celite pad andwashed thoroughly with dichloromethane (10 mL). Ethyl chloroformate(0.64 mL) was added to the filtrate at 0° C. and stirred at roomtemperature for 4 h. The reaction mixture was quenched with ice waterand extracted with dichloromethane (3×10 mL). The combined organiclayers were washed with 1N hydrochloride solution (10 mL), brine (10mL), dried over sodium sulfate, filtered and concentrated to affordethyl 2-(2-fluoro-4-isopropoxyphenyl)-2-oxoacetate (200 mg, 0.787 mmol,48% yield) as a colorless liquid. MS (ESI) m/z 255.28 [M+1]⁺.

C. Ethyl 2,2-difluoro-2-(2-fluoro-4-isopropoxyphenyl)acetate

Ethyl 2-(2-fluoro-4-isopropoxyphenyl)-2-oxoacetate (200 mg, 0.787 mmol)was added into diethylamino sulfur trifluoride (0.4 mL) at 0° C. andstirred at room temperature for 16 h. The reaction mixture was quenchedwith aqueous sodium bicarbonate solution and extracted with ethylacetate (3×10 mL). The combined organic layers were washed with brine(10 mL), dried over sodium sulfate, filtered and concentrated. Obtainedcrude product was purified by flash column chromatography (100-200silica gel, 10% ethyl acetate in pet ether) to afford ethyl2,2-difluoro-2-(2-fluoro-4-isopropoxyphenyl)acetate (200 mg, 0.72 mmol,92% yield) as a colourless liquid. MS (ESI) m/z 276.1 [M+1]⁺.

D. 2,2-Difluoro-2-(2-fluoro-4-isopropoxyphenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(2-fluoro-4-isopropoxyphenyl)acetate (200 mg, 0.72 mmol)in mixture of tetrahydrofuran:methanol:water (10 mL, 1:1:1) was addedlithium hydroxide monohydrate (91 mg, 2.17 mmol) and stirred at roomtemperature for 16 h. The reaction mixture was concentrated underreduced pressure and the resultant residue was dissolved in water (10mL) and washed with ethyl acetate (2×10 mL). The aqueous layer wasacidified with 1N hydrochloride aqueous solution and extracted withethyl acetate (3×10 mL). The combined organic layers were washed withbrine (10 mL), dried over sodium sulfate, filtered and concentrated toafford 2,2-difluoro-2-(2-fluoro-4-isopropoxyphenyl)acetic acid (160 mg,0.65 mmol, 89% yield) as semi-solid compound.

E.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-fluoro-4-isopropoxyphenyl)acetamide

To an ice cold solution of2,2-difluoro-2-(2-fluoro-4-isopropoxyphenyl)acetic acid (289 mg, 1.16mmol) in pyridine (9 mL) was added phosphorus oxychloride (0.27 mL, 2.9mmol) in drop wise and stirred at 0-5° C. for 1 h. Then,3-(5-(aminomethyl)-1-oxoisoindolin-2-yl) piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) was added into the reaction mixtureand stirred at room temperature for 1 h. The reaction mixture wasbasified with aqueous saturated sodium bicarbonate solution andextracted with ethyl acetate (3×15 mL). The combined organic layers werewashed with brine (15 mL), dried over sodium sulfate, filtered andconcentrated. The resultant crude product was purified by Reveleris C-18reversed phase column chromatography (50-55% acetonitrile in 0.1%aqueous formic acid) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-fluoro-4-isopropoxyphenyl)acetamide(60 mg, 0.12 mmol, 12% yield) as white solid. MS (ESI) m/z 503.99[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.59 (d, J=7.2 Hz,1H), 7.70 (d, J=7.6 Hz, 1H), 7.48 (dd, J=8.8, 8.7 Hz, 1H), 7.47 (s, 1H),7.41 (d, J=8.0 Hz, 1H), 6.96 (dd, J=13.2, 2.0 Hz, 1H), 6.87 (dd, J=8.3,2.0 Hz, 1H), 5.11 (dd, J=13.2, 5.2 Hz, 1H), 4.71 (sep, J=6.0 Hz, 1H),4.48 (d, J=6.4 Hz, 2H), 4.45 (d, J=17.2 Hz, 1H), 4.31 (d, J=18.0 Hz,1H), 2.95-2.87 (m, 1H), 2.62-2.58 (m, 1H), 2.41-2.37 (m, 1H), 2.02-1.99(m, 1H), 1.28 (d, J=5.6 Hz, 6H).

Example 60N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(morpholinomethyl)phenyl)acetamide

A. Ethyl 2,2-difluoro-2-(3-(morpholinomethyl)phenyl)acetate

To a stirred solution of ethyl 2,2-difluoro-2-(3-formylphenyl)acetate(1.2 g, 5.26 mmol) in ethanol (25 mL) was added morpholine (0.91 g,10.52 mmol), acetic acid (0.63 mL, 10.52 mmol) and stirred at 0° C. for1 h and then added sodium cyanoborohydride (0.661 g 10.52 mmol) andstirred at room temperature for 3 h. The reaction mixture was quenchedwith water (50 mL) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×20 mL), brine (30 mL),dried over sodium sulphate and concentrated to afford ethyl2,2-difluoro-2-(3-(morpholinomethyl)phenyl)acetate (0.8 g, 2.67 mmol,51% yield) as brown liquid. LCMS (ESI) m/z 300.0.

B. 2,2-Difluoro-2-(3-(morpholinomethyl)phenyl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(3-(morpholinomethyl)phenyl)acetate (0.8 g, 2.67 mmol) inmethanol/tetrahydrofuran/water mixture (15 mL, 1:1:1) was added lithiumhydroxide monohydrate (337 mg, 8.02 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous potassium bisulphate (20 mL)and extracted with ethyl acetate (2×40 mL). The combined organic layerswere washed with brine (20 mL), dried over sodium sulphate andconcentrated to afford 2,2-difluoro-2-(3-(morpholinomethyl)phenyl)aceticacid (600 mg, 2.21 mmol, 82% yield) as a brown solid. LCMS (ESI) m/z272.

C.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(morpholinomethyl)phenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(3-(morpholinomethyl)phenyl)acetic acid acid (290 mg,1.06 mmol) and3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.970 mmol) in N,N-dimethylformamide (20 mL) wasadded N,N-diisopropylethylamine (0.6 mL, 3.33 mmol) followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (553.3 mg, 1.45 mmol) and stirred at roomtemperature for 4 h. The reaction mixture was diluted with water (50 mL)and extracted with ethyl acetate (2×40 mL). The combined organic layerswere washed with brine (30 mL), dried over sodium sulphate, concentratedand dried under vacuum. The product was purified by Reveleris C-18reversed phase column using 40% acetonitrile in aqueous formic acid(0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(morpholinomethyl)phenyl)acetamide (40 mg, 0.06 mmol, 8% yield) as an off-white solid. LCMS (ESI)m/z 526.7 [M+1]⁺. ¹H NMR (300 MHz, TFA-d₄) 6=8.03-7.92 (m, 2H), 7.83 (brs, 1H), 7.72 (br s, 2H), 7.64-7.54 (m, 2H), 5.64-5.0 (m, 1H), 4.80 (brs, 2H), 4.73 (br s, 2H), 4.6 (br s, 2H), 4.4 (s, 2H), 4.08 (t, J=11.7Hz, 2H), 3.73 (d, J=11.7 Hz, 1H), 3.51 (d, J=12.1 Hz, 1H), 3.33-3.04 (m,2H), 2.92-2.61 (m, 1H), 2.53 (s, 1H).

Example 61N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)acetamide

A. 1-(4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl)ethanone

To a stirred solution of 1-(4-fluoro-2-hydroxyphenyl)ethanone (1 g, 6.48mmol) in N,N-dimethylformamide (20 mL) was added1,1,1-trifluoro-2-iodoethane (0.64 mL, 6.48 mmol) followed by potassiumcarbonate (2.68 g, 19.46 mmol) and stirred at 90° C. for 16 h. Thereaction mixture was diluted with ice water (30 mL) and extracted withethyl acetate (3×20 mL). The combined organic layers were washed withwater (20 mL), brine (20 mL), dried over sodium sulfate, filtered andsolvent was concentrated to afford1-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)ethanone (325 mg, 1.36 mmol,20% yield) as a colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.90 (dd,J=6.8, 6.8 Hz, 1H), 6.85-6.81 (m, 1H), 6.61 (dd, J=2.0, 2.4 Hz, 1H),4.42-4.38 (m, 2H), 2.61 (s, 3H).

B. Ethyl 2-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)-2-oxoacetate

To a stirred solution of1-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)ethanone (320 mg, 1.35 mmol)in pyridine (10 mL) was added selenium dioxide (376 mg, 3.38 mmol) atroom temperature. The reaction mixture was stirred at 100° C. for 16 h.The reaction mixture was filtered through celite pad and washed withdichloromethane (10 mL). Ethyl chloroformate (0.64 mL) was added to thefiltrate at 0° C. and stirred at room temperature for 4 h. The reactionmixture was quenched with ice water and extracted with dichloromethane(3×10 mL). The combined organic layers were washed with 1N hydrochloridesolution (15 mL), brine (10 mL), dried over sodium sulfate, filtered andconcentrated to afford ethyl2-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)-2-oxoacetate (300 mg, 1.02mmol, 75% yield) as a colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ7.99-7.95 (m, 1H), 6.94-6.89 (m, 1H), 6.66 (dd, J=2.4, 9.6 Hz, 1H),4.42-4.35 (m, 4H), 1.38 (t, J=7.6 Hz, 3H).

C. Ethyl2,2-difluoro-2-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)acetate

Ethyl 2-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)-2-oxoacetate (300 mg,1.02 mmol) was added into Diethylamino sulfur trifluoride (DAST, 0.9 mL)at 0° C. and stirred at room temperature for 16 h. The reaction mixturewas quenched with aqueous sodium bicarbonate solution and extracted withethyl acetate (3×10 mL). The combined organic layers were washed withbrine (10 mL), dried over sodium sulfate, filtered and concentrated.Obtained crude was purified by column chromatography (100-200 silicagel, 10% ethyl acetate in pet ether) to afford ethyl2,2-difluoro-2-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)acetate (250mg, 0.79 mmol, 77% yield) as a colourless liquid. ¹H NMR (300 MHz,CDCl₃) δ 7.71-7.66 (m, 1H), 6.91-6.85 (m, 1H), 6.66 (d, J=9.6 Hz, 1H),4.39-4.28 (m, 4H), 1.33 (t, J=4.2 Hz, 3H).

D. 2,2-Difluoro-2-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(4-fluoro-2-(2,2,2-trifluoro ethoxy) phenyl)acetate (390mg, 1.23 mmol) in tetrahydrofuran:methanol:water (12 mL, 1:1:1) wasadded lithium hydroxide monohydrate (155 mg, 3.70 mmol) and stirred atroom temperature for 16 h. The reaction mixture was concentrated underreduced pressure and obtained crude was dissolved in water (10 mL) andwashed with ethyl acetate (2×10 mL). Aqueous layer was acidified with 1Nhydrochloride aqueous solution and extracted with ethyl acetate (3×10mL). The combined organic layers were washed with brine (10 mL), driedover sodium sulfate, filtered and solvent was concentrated to afford2,2-difluoro-2-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)acetic acid(280 mg, 0.98 mmol, 79% yield) as semi-solid compound. ¹H NMR (400 MHz,CDCl₃) δ 7.72-7.69 (m, 1H), 6.91-6.87 (m, 1H), 6.66 (d, J=9.2 Hz, 1H),6.57 (brs, 1H), 4.39-4.34 (m, 2H).

E.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)acetamide

To an ice cold solution of2,2-difluoro-2-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)acetic acid(280 mg, 0.97 mmol) in pyridine (9 mL) was added phosphorus oxychloride(0.27 mL, 2.9 mmol) drop wise and stirred at 0-5° C. for 1 h. Then,3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) was added into the reaction mixtureand stirred at room temperature for 1 h. The reaction mixture wasbasified with aqueous saturated sodium bicarbonate solution andextracted with ethyl acetate (3×15 mL). The combined organic layers werewashed with brine (15 mL), dried over sodium sulfate, filtered andconcentrated. The resultant residue was purified by Reveleris C-18reversed phase column chromatography (50-55% acetonitrile in 0.1%aqueous formic acid) to giveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)acetamide(45 mg, 0.08 mmol, 8% yield) as white solid. MS (ESI) m/z 544.03 [M+1]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.44 (t, J=5.7 Hz, 1H), 7.70(d, J=7.8 Hz, 1H), 7.64 (dd, J=9.0, 6.6 Hz, 1H), 8.49 (s, 1H), 7.42 (d,J=8.1 Hz, 1H), 7.26 (dd, J=11.1, 0.6 Hz, 1H), 7.02 (ddd, J=10.8, 8.7,2.4 Hz, 1H), 5.11 (dd, J=13.2, 5.1 Hz, 1H), 4.81 (q, J=8.7 Hz, 2H), 4.45(d, J=7.2 Hz, 2H), 4.44 (d, J=16.2 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H),2.93-2.90 (m, 1H), 2.63-2.54 (m, 1H), 2.45-2.36 (m, 1H), 2.01-1.98 (m,1H).

Example 62N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxy-2-methylphenyl)acetamide

A. 1-(4-Isopropoxy-2-methylphenyl)ethanone

To a stirred solution of 1-(4-hydroxy-2-methylphenyl)ethanone (2.0 g,13.333 mmol) in N,N-dimethylformamide (20 mL) was added potassiumcarbonate (5.5 g, 49.0 mmol) followed by isopropyl iodide (2 mL, 20.0mmol) and stirred at 80° C. for 4 h. The reaction mixture was filteredand water (20 mL) was added and extracted with ethyl acetate (2×40 mL).The combined organic layers were washed with brine (30 mL), dried oversodium sulphate and concentrated. The resultant residue was purified bycolumn chromatography (100-200 silica) using 0-10% ethyl acetate inhexanes to afford 1-(4-isopropoxy-2-methylphenyl)ethanone (1.58 g, 8.229mmol, 62% yield). MS (ESI) m/z 193.48[M+1]⁺.

B. Ethyl 2-(4-isopropoxy-2-methylphenyl)-2-oxoacetate

To a stirred solution of 1-(4-isopropoxy-2-methylphenyl)ethanone (1.58g, 8.229 mmol mmol) in pyridine (30 mL) was added selenium dioxide (1.82g, 16.46 mmol) and stirred for 16 h at 100° C. The reaction mixture wasdiluted with dichloromethane (40 mL) and filtered through Celite pad. Tothe filtrate was added ethyl chloroformate (3 mL) at 0° C. and stirredfor 2 h. The reaction mixture was neutralized with 1N aqueoushydrochloric acid (up to pH-4) and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with water (2×10 mL), brine(10 mL), dried over sodium sulphate and concentrated. The resultantresidue was purified by column chromatography (100-200 silica) using 10%ethyl acetate in pet ether to afford ethyl2-(4-isopropoxy-2-methylphenyl)-2-oxoacetate (1.0 g, 4.01 mmol, 49%) asa colorless liquid. MS (ESI) m/z 251.40 [M+1]⁺.

C. Ethyl 2,2-difluoro-2-(4-isopropoxy-2-methylphenyl)acetate

To a stirred solution of ethyl2-(4-isopropoxy-2-methylphenyl)-2-oxoacetate (1.0 g, 4.01 mmol) wasreacted with diethyl amino sulfur trifluoride (1.32 mL, 10.025 mmol) andstirred for 12 h at room temperature. The reaction mixture wasneutralized with aqueous saturated sodium bicarbonate (up to pH-8) andextracted with ethyl acetate (3×50 mL). The combined organic layer waswashed with water (2×10 mL), brine (10 mL), dried over sodium sulphateand concentrated to afford ethyl2,2-difluoro-2-(4-isopropoxy-2-methylphenyl)acetate (990 mg, 3.639 mmol,91%) as a liquid. GC-MS (m/z) 272.2 [M]⁺.

D. 2,2-Difluoro-2-(4-isopropoxy-2-methylphenyl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(4-isopropoxy-2-methylphenyl)acetate (990 mg, 3.694 mmol)in tetrahydrofuran:methanol:water mixture (1:1:1, 10 mL) was addedlithium hydroxide (916 mg, 21.838 mmol) and stirred at room temperaturefor 2 h. The reaction mixture was concentrated and the residue wasneutralized with 10% aqueous hydrochloric acid (10 mL) and extractedwith ethyl acetate (2×20 mL). The combined organic layers were washedwith brine (20 mL), dried over sodium sulphate and concentrated toafford 2,2-difluoro-2-(4-isopropoxy-2-methylphenyl)acetic acid (719 mg,2.618 mmol, 81% yield) as an brown solid. ¹H NMR (400 MHz, CDCl₃) δ ppm9.59 (br s, 1H) 7.49 (d, J=8.80 Hz, 1H) 6.58-6.85 (m, 2H) 4.41-4.67 (m,1H) 2.41 (s, 3H) 1.34 (m, 6H).

E.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxy-2-methylphenyl)acetamide

To a stirred solution of2,2-difluoro-2-(4-isopropoxy-2-methylphenyl)acetic acid (236 mg, 0.968mmol) in pyridine (25 mL) was added phosphoryl chloride (0.3 mL, 2.16mmol) dropwise and stirred at 0-5° C. for 1 h and then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.968 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layer was washed with water (2×50 mL), brine (50 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase Grace column chromatographyusing 40-50% acetonitrile in aqueous formic acid (0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxy-2-methylphenyl)acetamide(79 mg, 0.158 mmol, 16% yield) as an off white solid. MS (ESI) m/z500.2329 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.98 (s, 1H), 9.51 (brt, J=6.05 Hz, 1H), 7.69 (d, J=7.70 Hz, 1H), 7.51-7.28 (m, 3H), 6.83 (s,2H), 5.11 (br dd, J=13.20, 5.14 Hz, 1H), 4.66 (dt, J=12.10, 6.05 Hz,1H), 4.51-4.25 (m, 4H), 2.99-2.82 (m, 1H), 2.67-2.54 (m, 1H), 2.46-2.30(m, 1H), 2.28 (s, 3H), 2.07-1.95 (m, 1H), 1.26 (m, 6H).

Example 63N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxy-3-methylphenyl)acetamide

A. 1-(4-Isopropoxy-3-methylphenyl)ethanone

To a stirred solution of 1-(4-hydroxy-3-methylphenyl)ethanone (3.0 g,19.97 mmol) in N,N-dimethyl formamide (20 mL) was added potassiumcarbonate (8.3 g, 59.91 mmol), isopropyl iodide (4.0 g, 23.96 mmol) atroom temperature and stirred at 100° C. for 4 h. The reaction mixturewas quenched with water (150 mL) and extracted with ethyl acetate (2×100mL). The combined organic layers were washed with water (2×100 mL),brine (100 mL), dried over sodium sulphate and concentrated to afford1-(4-isopropoxy-3-methylphenyl)ethanone (3.2 g, 16.66 mmol, 84% yield).LCMS (ESI) m/z 193.3 [M+1]⁺.

B. Ethyl 2-(4-isopropoxy-3-methylphenyl)-2-oxoacetate

To a stirred solution of 1-(4-isopropoxy-3-methylphenyl)ethanone (3.2 g,16.66 mmol) in pyridine (15 mL) was added selenium dioxide (4.6 g, 41.66mmol) and stirred at 100° C. for 16 h. The reaction mixture was dilutedwith dichloromethane (30 mL) and filtered through Celite pad. To thefiltrate was added ethyl chloroformate (9 mL) at 0° C. and stirred atroom temperature for 3 h. The reaction mixture was neutralized with 1Naqueous hydrochloric acid (up to pH-4) and extracted with ethyl acetate(2×100 mL). The combined organic layers were washed with water (2×50mL), brine (50 mL), dried over sodium sulphate and concentrated toafford ethyl 2-(4-isopropoxy-3-methylphenyl)-2-oxoacetate (2.5 g, 10.0mmol, 60% yield). LCMS (ESI) m/z 251.28 [M+1]⁺.

C. Ethyl 2,2-difluoro-2-(4-isopropoxy-3-methylphenyl)acetate

To a stirred solution of ethyl2-(4-isopropoxy-3-methylphenyl)-2-oxoacetate (500 mg, 2.00 mmol) wasreacted with diethyl amino sulfur trifluoride (2.5 g, 15.26 mmol) andstirred at room temperature for 16 h. The reaction mixture wasneutralized with aqueous saturated sodium bicarbonate (up to pH-8) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×30 mL), brine (30 mL) and dried over sodiumsulphate and was concentrated to give ethyl2,2-difluoro-2-(4-isopropoxy-3-methylphenyl)acetate (450 mg, 1.65 mmol,83% yield). GCMS (m/z) 272.2 [M]⁺.

D. 2,2-Difluoro-2-(4-isopropoxy-3-methylphenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(4-isopropoxy-3-methylphenyl)acetate (450 mg, 1.65 mmol)in tetrahydrofuran-methanol-water (20 mL, 1:1:1) was added lithiumhydroxide monohydrate (208 mg, 4.96 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous hydrochloric acid (5 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine (20 mL), dried over sodium sulphate and concentratedto give 2,2-difluoro-2-(4-isopropoxy-3-methylphenyl)acetic acid (200 mg,0.81 mmol, 50% yield). LCMS (ESI) m/z 243.34 [M−1]⁺.

E.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxy-3-methylphenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(4-isopropoxy-3-methylphenyl)acetic acid (200 mg, 0.81mmol) in pyridine (5 mL) was added phosphoryl chloride (0.3 mL, 2.45mmol) and stirred at 0-5° C. for 1 h. Then added 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (253 mg,0.81 mmol) and stirred at room temperature for 1 h. The reaction mixturewas neutralized with aqueous saturated sodium bicarbonate (up to pH-8)and extracted with ethyl acetate (2×25 mL). The combined organic layerswere washed with water (25 mL), brine (25 mL), dried over sodiumsulphate and concentrated. The resultant residue was purified byReveleris C-18 reversed phase column chromatography using 40-45%acetonitrile in aqueous formic acid (0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxy-3-methylphenyl)acetamide(90 mg, 0.18 mmol, 22.0% yield) as an off white solid. LCMS (ESI) m/z500.57 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ=10.98 (s, 1H), 9.52 (br t,J=6.1 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.44-7.26 (m, 2H), 7.06 (d, J=8.3Hz, 1H), 5.11 (dd, J=4.9, 13.2 Hz, 1H), 4.72-4.60 (m, 1H), 4.50-4.20 (m,4H), 3.00-2.83 (m, 1H), 2.67-2.54 (m, 1H), 2.44-2.29 (m, 1H), 2.14 (s,3H), 2.05-1.95 (m, 1H), 1.29 (d, J=6.4 Hz, 6H).

Example 64N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-fluoro-4-isopropoxyphenyl)acetamide

A. 1-(3-Fluoro-4-isopropoxyphenyl)ethanone

To a stirred solution of 1-(3-fluoro-4-hydroxyphenyl)ethanone (3.0 g,19.46 mmol) in N,N-dimethylformamide (20 mL) was added potassiumcarbonate (8.0 g, 58.38 mmol), isopropyl iodide (3.9 g, 23.35 mmol) atroom temperature and stirred at 100° C. for 4 h. The reaction mixturewas quenched with water (150 mL) and extracted with ethyl acetate (2×100mL). The combined organic layers were washed with water (2×100 mL),brine (100 mL), dried over sodium sulphate and concentrated to afford1-(3-fluoro-4-isopropoxyphenyl)ethanone (3.1 g, 15.81 mmol, 81% yield).LCMS (ESI) m/z 197.3 [M+1]⁺.

B. Ethyl 2-(3-fluoro-4-isopropoxyphenyl)-2-oxoacetate

To a stirred solution of 1-(3-fluoro-4-isopropoxyphenyl)ethanone (3.1 g,15.81 mmol) in pyridine (15 mL) was added selenium dioxide (4.6 g, 39.54mmol) and stirred at 100° C. for 16 h. The reaction mixture was dilutedwith dichloromethane (30 mL) and filtered through Celite pad. To thefiltrate was added ethyl chloroformate (9 mL) at 0° C. and stirred atroom temperature for 3 h. The reaction mixture was neutralized with 1Naqueous hydrochloric acid (up to pH-4) and extracted with ethyl acetate(2×100 mL). The combined organic layers were washed with water (2×50mL), brine (50 mL), dried over sodium sulphate and concentrated toafford ethyl 2-(3-fluoro-4-isopropoxyphenyl)-2-oxoacetate (2.5 g, 9.84mmol, 62% yield). LCMS (ESI) m/z 255.28 [M+1]⁺.

C. Ethyl 2,2-difluoro-2-(3-fluoro-4-isopropoxyphenyl)acetate

To a stirred solution of ethyl2-(3-fluoro-4-isopropoxyphenyl)-2-oxoacetate (1.2 g, 4.72 mmol) wasadded diethyl amino sulfur trifluoride (3.1 g, 19.23 mmol) and stirredat room temperature for 16 h. The reaction mixture was neutralized withaqueous saturated sodium bicarbonate (up to pH-8) and extracted withethyl acetate (3×100 mL). The combined organic layers were washed withwater (2×50 mL), brine (50 mL), dried over sodium sulphate andconcentrated to afford ethyl2,2-difluoro-2-(3-fluoro-4-isopropoxyphenyl)acetate (900 mg, 3.26 mmol,69% yield). GCMS (m/z) 276.2 [M]⁺.

D. 2,2-Difluoro-2-(3-fluoro-4-isopropoxyphenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(3-fluoro-4-isopropoxyphenyl)acetate (900 mg, 3.26 mmol)in tetrahydrofuran-methanol-water (20 mL, 1:1:1) was added lithiumhydroxide monohydrate (410 mg, 9.78 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous hydrochloric acid (5 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine (20 mL), dried over sodium sulphate and concentratedto afford 2,2-difluoro-2-(3-fluoro-4-isopropoxyphenyl)acetic acid (700mg, 2.82 mmol, 87% yield). LCMS (ESI) m/z 247.52 [M−1]⁺.

E.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-fluoro-4-isopropoxyphenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(3-fluoro-4-isopropoxyphenyl)acetic acid (300 mg, 1.20mmol) in pyridine (10 mL) was added phosphoryl chloride (0.4 mL, 3.62mmol) and stirred at 0-5° C. for 1 h. Then added 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (374 mg,1.20 mmol) and stirred at room temperature for 1 h. The reaction mixturewas neutralized with aqueous saturated sodium bicarbonate (up to pH-8)and extracted with ethyl acetate (2×25 mL). The combined organic layerswere washed with water (25 mL), brine (25 mL), dried over sodiumsulphate and concentrated. The resultant residue was purified byReveleris C-18 reversed phase column chromatography using 35-40%acetonitrile in aqueous formic acid (0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-fluoro-4-isopropoxyphenyl)acetamide (80 mg, 0.15 mmol, 13.0% yield) as an off white solid. LCMS(ESI) m/z 504.56 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ=10.98 (s, 1H), 9.60(br t, J=6.1 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.45-7.26 (m, 5H), 5.10(dd, J=5.1, 13.5 Hz, 1H), 4.73 (m, 1H), 4.50-4.23 (m, 4H), 2.98-2.85 (m,1H), 2.67-2.55 (m, 1H), 2.45-2.30 (m, 1H), 2.04-1.95 (m, 1H), 1.30 (d,J=5.9 Hz, 6H).

Example 652-(3-Chloro-4-isopropoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. 1-(3-Chloro-4-isopropoxyphenyl)ethanone

To a stirred solution of 1-(3-chloro-4-hydroxyphenyl)ethanone (2.5 g,14.62 mmol) in N,N-dimethylformamide (30 mL) was added 2-iodopropane(2.98 g, 17.54 mmol) followed by potassium carbonate (5.04 g, 36.55mmol) and stirred at 90° C. for 16 h. The reaction mixture was dilutedwith ice water (40 mL) and extracted with ethyl acetate (3×30 mL). Thecombined organic layers were washed with water (30 mL), brine (30 mL),dried over sodium sulfate, filtered and concentrated to afford1-(3-chloro-4-isopropoxyphenyl)ethanone (2.3 g, 10.84 mmol, 74% yield)as a colorless liquid. MS (ESI) m/z 213.23 [M]⁺.

B. Ethyl 2-(3-chloro-4-isopropoxyphenyl)-2-oxoacetate

To a stirred solution of 1-(3-chloro-4-isopropoxyphenyl)ethanone (2 g,8.26 mmol) in pyridine (30 mL) was added selenium dioxide (2.69 g, 24.79mmol) at room temperature. The reaction mixture was stirred at 100° C.for 16 h. The reaction mixture was filtered through a Celite pad andwashed with dichloromethane (30 mL). Ethyl chloroformate (6 mL) wasadded to the filtrate at 0° C. and stirred at room temperature for 4 h.The reaction mixture was quenched with ice water and extracted withdichloromethane (3×30 mL). The combined organic layers were washed with1N hydrochloride solution (30 mL), brine (30 mL), dried over sodiumsulfate, filtered and concentrated to afford ethyl2-(3-chloro-4-isopropoxyphenyl)-2-oxoacetate (1.8 g, 6.66 mmol, 80%yield) as a colourless liquid. ¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J=2.0Hz, 1H), 7.92 (dd, J=8.8, 2.8 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 4.71(sep, J=6.2 Hz, 1H), 4.44 (q, J=6.8 Hz, 2H), 1.44 (d, J=6.5 Hz, 6H),1.38 (t, J=7.2 Hz, 3H).

C. Ethyl 2-(3-chloro-4-isopropoxyphenyl)-2,2-difluoroacetate

Diethylamino sulfur trifluoride (1.47 mL) was added into ethyl2-(3-chloro-4-isopropoxyphenyl)-2-oxoacetate (1 g, 3.7 mmol) at 0° C.and stirred at room temperature for 16 h. The reaction mixture wasquenched with aqueous sodium bicarbonate solution and extracted withethyl acetate (3×15 mL). The combined organic layers were washed withbrine (15 mL), dried over sodium sulfate, filtered and concentrated.Obtained crude was purified by column chromatography (100-200 silicagel, 10% ethyl acetate in pet ether) to afford ethyl2-(3-chloro-4-isopropoxyphenyl)-2,2-difluoroacetate (900 mg, 3.08 mmol,89% yield) as a colourless liquid. MS (ESI) m/z 293.1 [M+1]⁺.

D. 2-(3-Chloro-4-isopropoxyphenyl)-2,2-difluoroacetic acid

To a stirred solution of ethyl2-(3-chloro-4-isopropoxyphenyl)-2,2-difluoroacetate (0.45 g, 1.54 mmol)in tetrahydrofuran:methanol:water (15 mL, 1:1:1) was added lithiumhydroxide monohydrate (195 mg, 4.54 mmol) and stirred at roomtemperature for 16 h. The volatiles were removed under reduced pressureand the obtained residue was dissolved in water (10 mL), washed withethyl acetate (2×10 mL). Aqueous layer was acidified with 1Nhydrochloride solution and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were washed with brine (10 mL), dried oversodium sulfate, filtered and concentrated to afford2-(3-chloro-4-isopropoxyphenyl)-2,2-difluoroacetic acid (300 mg, 1.13mmol, 74% yield) as semi-solid compound. ¹H NMR (400 MHz, CDCl₃) δ 8.41(brs, 1H), 7.65 (d, J=2.1 Hz, 1H), 7.47 (dd, J=8.7, 2.1 Hz, 1H), 6.97(dd, J=5.1, 8.7 Hz, 1H), 4.62 (sep, J=5.7 Hz, 1H), 1.40 (d, J=6.3 Hz,6H).

E.2-(3-Chloro-4-isopropoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To an ice cold solution of2-(3-chloro-4-isopropoxyphenyl)-2,2-difluoroacetic acid (235 mg, 0.89mmol) in pyridine (6 mL) was added phosphorus oxychloride (0.23 mL, 2.43mmol) in dropwise and stirred at 0-5° C. for 1 h. Then,3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (250 mg, 0.81 mmol) was added and stirred at roomtemperature for 2 h. The reaction mixture was basified with aqueoussaturated sodium bicarbonate solution and extracted with ethyl acetate(3×15 mL). The combined organic layers were washed with water (15 mL),brine (15 mL), dried over sodium sulfate, filtered and concentrated. Theresultant residue was purified by Reveleris C-18 reversed phase columnchromatography (50-55% acetonitrile in 0.1% aqueous formic acid) to give2-(3-chloro-4-isopropoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide (60 mg, 0.11 mmol, 14% yield) as white solid. MS (ESI) m/z520.01 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.62 (t, J=5.7Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.49 (dd,J=8.7, 2.1 Hz, 1H), 7.41 (s, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.31 (d, J=8.7Hz, 1H), 5.11 (dd, J=13.2, 5.4 Hz, 1H), 4.76 (sep, J=6.3 Hz, 1H), 4.45(d, J=5.7 Hz, 2H), 4.42 (d, J=18.0 Hz, 1H), 4.28 (d, J=17.7, 1H),2.93-2.87 (m, 1H), 2.63-2.57 (m, 1H), 2.40-2.30 (m, 1H), 2.04-1.94 (m,1H), 1.31 (d, J=5.7 Hz, 6H).

Example 66N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-methyl-4-(trifluoromethoxy)phenyl)acetamide

A. Ethyl 2,2-difluoro-2-(2-methyl-4-(trifluoromethoxy)phenyl)acetate

To a stirred solution of 1-iodo-2-methyl-4-(trifluoromethoxy)benzene(1.0 g, 3.31 mmol) in dimethylsulfoxide (13 mL) was added copper (546mg, 8.60 mmol) and ethyl 2-bromo-2,2-difluoroacetate (0.638 mL 4.96mmol) at room temperature and stirred at 55° C. for 2 h. The reactionmixture was neutralized with aqueous saturated ammonium chloride (50 mL)solution and extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with water (2×100 mL), brine (100 mL), driedover sodium sulphate and concentrated to afford ethyl2,2-difluoro-2-(2-methyl-4-(trifluoromethoxy)phenyl)acetate (900 mg,3.02 mmol, 91%). ¹H NMR (400 MHz, CDCl₃) δ 7.65-7.58 (d, 1H), 7.18-7.02(m, 2H), 4.41-4.25 (m, 2H), 2.43 (s, 3H), 1.36-1.29 (m, 3H). (Ethylacetate traces indicated along with the product in the ¹H NMR)

B. 2,2-Difluoro-2-(2-methyl-4-(trifluoromethoxy)phenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(2-methyl-4-(trifluoromethoxy)phenyl)acetate (900 mg,3.020 mmol) in tetrahydrofuran:methanol:water mixture (30 mL, 1:1:1) wasadded lithium hydroxide monohydrate (634 mg, 15.106 mmol) and stirred atroom temperature for 4 h. The reaction mixture was concentrated and theresidue was neutralized with saturated potassium bisulphate (25 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine (50 mL), dried over sodium sulphate and concentratedto afford 2,2-difluoro-2-(2-methyl-4-(trifluoromethoxy)phenyl)aceticacid (450 mg, 1.66 mmol, 55% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.65-7.49(d, J=9.2 Hz, 1H), 7.20-7.16 (m, 2H), 2.18 (s, 3H).

C.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-methyl-4-(trifluoromethoxy)phenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(2-methyl-4-(trifluoromethoxy)phenyl)acetic acid (261 mg,0.968 mmol) in pyridine was added phosphoryl chloride (0.27 mL, 2.906mmol) drop wise and stirred at 0-5° C. for 1 h. To this reaction mixturewas then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.968 mmol) and stirred at room temperature for30 min. The reaction mixture was neutralized with aqueous saturatedsodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with water (2×10 mL), brine(10 mL), dried over sodium sulphate and concentrated. The resultantresidue was purified by Reveleris C-18 reversed phase columnchromatography using 40-60% acetonitrile in aqueous formic acid (0.1%)to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-methyl-4-(trifluoromethoxy)phenyl)acetamide(60 mg, 0.114 mmol, 11% yield) as an off white solid. MS (ESI) m/z526.52 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.65 (t, J=5.9Hz, 1H), 7.73-7.63 (m, 2H), 7.46 (s, 1H), 7.43-7.38 (d, J=8.0 Hz, 1H),7.38-7.32 (m, 2H), 5.10 (dd, J=13.2, 5.1 Hz, 1H), 4.52-4.28 (m, 4H),2.96-2.85 (m, 1H), 2.68-2.53 (m, 1H), 2.47-2.31 (m, 4H), 2.08-1.94 (m,1H).

Example 67N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-fluoro-4-(trifluoromethoxy)phenyl)acetamide

A. 2-Fluoro-1-iodo-4-(trifluoromethoxy)benzene

To a stirred solution of 1-bromo-2-fluoro-4-(trifluoromethoxy)benzene(500 mg, 1.93 mmol) in 1,4-dioxane (10 mL) was added sodium iodide (579mg, 3.86 mmol), copper iodide (18 mg, 0.09 mmol) andtrans-N,N′-dimethylcyclohexane-1,2-diamine (30 mg, 0.11 mmol) at roomtemperature, then heated at 110° C. for 16 h. The reaction mixture wasquenched with water (10 mL) and extracted with ethyl acetate (3×10 mL).The combined organic layers were washed with water (10 mL), brine (10mL), dried over sodium sulfate, filtered and concentrated to afford2-fluoro-1-iodo-4-(trifluoromethoxy)benzene (400 mg, 1.3 mmol, 68%yield) as brown liquid. ¹H NMR (300 MHz, CDCl₃) δ 7.78 (dd, J=8.4, 6.9Hz, 1H), 6.98 (dd, J=8.1, 1.5 Hz, 1H), 6.84 (d, J=8.3 Hz, 1H).

B. Ethyl 2,2-difluoro-2-(2-fluoro-4-(trifluoromethoxy)phenyl)acetate

To a stirred solution of 2-fluoro-1-iodo-4-(trifluoromethoxy)benzene (1g, 3.27 mmol) in dimethylsulfoxide (20 mL) was added ethyl2-bromo-2,2-difluoroacetate (0.6 mL, 4.9 mmol) followed by copper (0.54g, 8.49 mmol) at RT and stirred at 60° C. for 6 h. The reaction mixturewas basified with aqueous saturated sodium bicarbonate solution andextracted with ethyl acetate (3×15 mL). The combined organic layers werewashed with water (15 mL), brine (15 mL), dried over sodium sulfate,filtered and concentrated. The obtained crude product was purified byflash chromatography (20% ethyl acetate in pet ether) to afford ethyl2,2-difluoro-2-(2-fluoro-4-(trifluoromethoxy)phenyl)acetate (800 mg,2.64 mmol, 81% yield) as a colorless liquid. MS (ESI) m/z 302.1 [M]⁺.

C. 2,2-Difluoro-2-(2-fluoro-4-(trifluoromethoxy)phenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(2-fluoro-4-(trifluoromethoxy)phenyl)acetate (800 mg,2.64 mmol) in mixture of tetrahydrofuran:methanol:water (15 mL, 1:1:1)was added lithium hydroxide monohydrate (333 mg, 7.94 mmol) and stirredat room temperature for 4 h. The volatiles were removed under reducedpressure and the obtained crude was dissolved in water (15 mL) andwashed with ethyl acetate (2×10 mL). Aqueous layer was acidified with 1Nhydrochloride aqueous solution and extracted with ethyl acetate (3×10mL). The combined organic layers were washed with brine (15 mL), driedover sodium sulfate, filtered and concentrated to afford2,2-difluoro-2-(2-fluoro-4-(trifluoromethoxy)phenyl)acetic acid (450 mg,1.64 mmol, 62% yield) as semi-solid compound. MS (ESI) m/z 298.1 [M]⁺.¹H NMR (400 MHz, CDCl₃) δ 7.70 (dd, J=9.6 Hz, 1.6 Hz, 1H), 7.14 (d,J=7.9 Hz, 1H), 7.06 (dd, J=7.8 Hz, 1.8 Hz, 1H), 5.02 (brs, 1H).

D.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-fluoro-4-(trifluoromethoxy)phenyl)acetamide

To an ice cold stirred solution of2,2-difluoro-2-(2-fluoro-4-(trifluoromethoxy) phenyl)acetic acid (274mg, 1.55 mmol) in pyridine (6 mL) was added phosphorus oxychloride (0.36mL, 3.87 mmol) dropwise and stirred at 0-5° C. for 1 h. Then, thereaction mixture was treated with3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (400 mg, 1.29 mmol) and stirred at room temperature for 2h. The reaction mixture was basified with aqueous saturated sodiumbicarbonate solution and extracted with ethyl acetate (3×15 mL). Thecombined organic layers were washed with water (15 mL), brine (15 mL),dried over sodium sulfate, filtered and concentrated. The resultantresidue was purified by Reveleris C-18 reversed phase columnchromatography (50-55% acetonitrile in 0.1% aqueous formic acid toaffordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-fluoro-4-(trifluoromethoxy)phenyl)acetamide(60 mg, 0.11 mmol, 9% yield) as white solid. MS (ESI) m/z 529.6 [M+1]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.76 (t, J=5.8 Hz, 1H), 7.82(dd, J=8.4, 8.3 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.63 (d, J=11.4 Hz,1H), 7.48 (s, 1H), 7.43-7.40 (m, 2H), 5.11 (dd, J=12.9, 4.8 Hz, 1H),4.50 (d, J=6.3 Hz, 2H), 4.46 (t, J=17.7 Hz, 1H), 4.31 (d, J=17.4, 1H),2.90-2.63 (m, 1H), 2.63-2.56 (m, 1H), 2.42-2.27 (m, 1H), 2.02-1.98 (m,1H).

Example 682-(5-Chloropyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. Ethyl 2-(5-chloropyridin-2-yl)-2,2-difluoroacetate

To a stirred solution of 5-chloro-2-iodopyridine (1.0 g, 4.18 mmol) indimethylsulfoxide (11 mL) was added copper (690 mg, 10.86 mmol) andethyl 2-bromo-2,2-difluoroacetate (1.01 g, 5.01 mmol) at roomtemperature and stirred at 55° C. for 6 h. The reaction mixture wasneutralized with saturated aqueous ammonium chloride solution andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with water (2×50 mL), brine (50 mL), dried over sodium sulphateand concentrated to afford ethyl2-(5-chloropyridin-2-yl)-2,2-difluoroacetate (700 mg, 2.98 mmol, 70%).GCMS (m/z) 235.1 [M]⁺.

B. 2-(5-Chloropyridin-2-yl)-2,2-difluoroacetic acid

To a stirred solution of ethyl2-(5-chloropyridin-2-yl)-2,2-difluoroacetate (800 mg, 3.40 mmol) intetrahydrofuran:methanol:water mixture (30 mL, 1:1:1) was added lithiumhydroxide monohydrate (429 mg, 10.21 mmol) and stirred at roomtemperature for 4 h. The reaction mixture was concentrated and theresidue was neutralized with saturated potassium bisulphate (20 mL) andextracted with ethyl acetate (2×25 mL). The combined organic layers werewashed with brine (25 mL), dried over sodium sulphate and concentratedto afford 2-(5-chloropyridin-2-yl)-2,2-difluoroacetic acid (400 mg, 1.94mmol, 57% yield). MS (ESI) m/z 208.30 [M+1]⁺.

C.2-(5-Chloropyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a cold (0° C.) stirred solution of2-(5-chloropyridin-2-yl)-2,2-difluoroacetic acid (200 mg, 0.96 mmol) inpyridine (20 mL) was added phosphoryl chloride (443 mg, 2.89 mmol)dropwise and stirred at 0-5° C. for 30 min. To this reaction mixture wasthen added 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.96 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with saturated aqueous sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×50 mL), brine (50 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase column chromatography using40-45% acetonitrile in aqueous formic acid (0.1%) to afford2-(5-chloropyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(65 mg, 0.14 mmol, 14% yield) as an off-white solid. MS (ESI) m/z 462.69[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ=10.99 (s, 1H), 9.69 (t, J=5.9 Hz,1H), 8.81 (d, J=2.2 Hz, 1H), 8.19 (dd, J=2.6, 8.4 Hz, 1H), 7.85 (d,J=8.4 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J=7.7 Hz,1H), 5.11 (dd, J=5.0, 13.0 Hz, 1H), 4.56-4.27 (m, 4H), 3.00-2.84 (m,1H), 2.74-2.55 (m, 1H), 2.45-2.22 (m, 1H), 2.09-1.91 (m, 1H).

Example 69N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-fluoropyridin-2-yl)acetamide

A. 5-Fluoro-2-iodopyridine

To a stirred solution of 2-bromo-5-fluoropyridine (2.5 g, 14.2 mmol) in1,4-dioxane (10 mL) was added sodium iodide (4.26 g, 28.4 mmol), copperiodide (135 mg, 0.71 mmol) followed bytrans-N,N-dimethylcyclohexane-1,2-diamine (0.24 mL, 1.56 mmol) at roomtemperature and stirred at 110° C. for 16 h. The reaction mixture wasquenched with water (30 mL) and extracted with ethyl acetate (3×25 mL).The combined organic layers were washed with water (25 mL), brine (25mL), dried over sodium sulfate, filtered and concentrated to afford5-fluoro-2-iodopyridine (2.2 g, 9.86 mmol, 71% yield) as brown liquid.LCMS (m/z) 224.3 [M⁺].

B. Ethyl 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate

To a stirred solution of 5-fluoro-2-iodopyridine (300 mg, 1.34 mmol) indimethylsulfoxide (3.4 mL) was added ethyl 2-bromo-2,2-difluoroacetate(409 mg, 2.02 mmol) followed by copper (22 mg, 3.49 mmol) at RT andstirred at 60° C. for 6 h. The reaction mixture was basified withaqueous saturated sodium bicarbonate solution and extracted with ethylacetate (3×10 mL). The combined organic layers were washed with water(10 mL), brine (10 mL), dried over sodium sulfate, filtered andconcentrated. The obtained crude was purified by silica gel columnchromatography (20% ethyl acetate in pet ether) to afford ethyl2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate (200 mg, 0.72 mmol, 54%yield) as a colorless liquid. MS (ESI) m/z 278 [M]⁺.

C. 2,2-Difluoro-2-(5-fluoropyridin-2-yl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate (250 mg, 1.14 mmol) inmixture of tetrahydrofuran:methanol:water (10 mL, 1:1:1) was addedlithium hydroxide monohydrate (144 mg, 3.42 mmol) and stirred at roomtemperature for 4 h. The volatiles were removed under reduced pressureand the obtained crude was dissolved in water (10 mL), washed with ethylacetate (2×10 mL). Aqueous layer was acidified with 1N hydrochlorideaqueous solution and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were washed with brine (10 mL), dried oversodium sulfate, filtered and concentrated to afford2,2-difluoro-2-(5-fluoropyridin-2-yl)acetic acid (150 mg, 0.78 mmol, 69%yield) as semi-solid compound. ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H),8.37 (brs, 1H), 7.84 (dd, J=8.8 Hz, 4.4 Hz, 1H), 7.64 (ddd, J=10.8 Hz,8.8 Hz, 2.4 Hz, 1H).

D.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-fluoropyridin-2-yl)acetamide

To an ice cold solution of 2,2-difluoro-2-(5-fluoropyridin-2-yl)aceticacid (221 mg, 1.16 mmol) in pyridine (6 mL) was added phosphorusoxychloride (0.27 mL, 2.91 mmol) dropwise and stirred at 0-5° C. for 1h. Then, 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) was added and stirred at roomtemperature for 2 h. The reaction mixture was basified with aqueoussaturated sodium bicarbonate solution and extracted with ethyl acetate(3×15 mL). The combined organic layers were washed with water (15 mL),brine (15 mL), dried over sodium sulfate, filtered and concentrated. Theresultant residue was purified by Reveleris C-18 reversed phase columnchromatography (50-55% acetonitrile in 0.1% aqueous formic acid toaffordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-fluoropyridin-2-yl)acetamide (60 mg, 0.11 mmol, 14% yield) as white solid. MS(ESI) m/z 446.7 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.67(t, J=5.7 Hz, 1H), 8.76 (d, J=2.4 Hz, 1H), 8.01-7.89 (m, 2H), 7.71 (d,J=7.8 Hz, 1H), 7.52 (s, 1H), 7.45 (d, J=8.1 Hz, 1H), 5.11 (dd, J=13.5,5.1 Hz, 1H), 4.50 (d, J=5.4 Hz, 2H), 4.47 (d, J=17.4 Hz, 1H), 4.32 (d,J=17.1, 1H), 2.98-2.84 (m, 1H), 2.66-2.58 (m, 1H), 2.43-2.30 (m, 1H),2.02-1.94 (m, 1H).

Example 702-(2,4-Difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. Ethyl 2-(2,4-difluorophenyl)-2,2-difluoroacetate

To a stirred solution of 2,4-difluoro-1-iodobenzene (800 mg, 3.33 mmol)in dimethyl sulfoxide (10 mL) was added ethyl2-bromo-2,2-difluoroacetate (1.01 g, 4.99 mmol), copper (550 mg, 8.65mmol) and stirred at 55° C. for 6 h. The reaction mixture wasneutralized with aqueous saturated ammonium chloride solution andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×50 mL), brine (50 mL), dried over sodium sulphateand concentrated to afford ethyl2-(2,4-difluorophenyl)-2,2-difluoroacetate (400 mg, 1.69 mmol, 51%) as abrown liquid. GCMS: 236.1[M]⁺.

B. 2-(2,4-Difluorophenyl)-2,2-difluoroacetic acid

To a stirred solution of ethyl2-(2,4-difluorophenyl)-2,2-difluoroacetate (400 mg, 1.69 mmol) inethanol:tetrahydrofuran:water (10 mL, 1:1:1) was added lithium hydroxide(214 mg, 5.08 mmol) and stirred at room temperature for 4 h. Thereaction mixture was concentrated and the residue was neutralized withsat. potassium hydrozensulphate (20 mL) and extracted with ethyl acetate(2×50 mL). The combined organic layer was washed with brine (25 mL),dried over sodium sulphate and concentrated to give2-(2,4-difluorophenyl)-2,2-difluoroacetic acid (250 mg, 1.20 mmol, 71%yield). MS (ESI) m/z 207.43 [M−1]⁺

C.2-(2,4-Difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a stirred cold (0° C.) solution of3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) in N,N-dimethylformamide (10 mL) wasadded 2-(2,4-difluorophenyl)-2,2-difluoroacetic acid (202 mg, 0.97 mmol)followed by diisopropylethylamine (0.52 mL, 2.91 mmol),1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (480 mg, 1.26 mmol) and stirred at roomtemperature for 16 h. The reaction mixture was diluted with water (100mL) and the solid obtained was filtered, washed with diethyl ether (20mL), dried and purified by column chromatography (100-200 silica) using4% methanol in dichloromethane as eluent to afford2-(2,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(60 mg, 0.129 mmol, 13% yield) as an off white solid. MS (ESI) m/z463.68 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ=10.98 (s, 1H), 9.72 (br t,J=5.9 Hz, 1H), 7.78-7.65 (m, 2H), 7.55-7.34 (m, 3H), 7.29-7.18 (m, 1H),5.11 (br dd, J=5.1, 13.2 Hz, 1H), 4.56-4.16 (m, 4H), 3.08-2.80 (m, 1H),2.75-2.59 (m, 1H), 2.44-2.32 (m, 1H), 2.06-1.92 (m, 1H).

Example 712-(4-Bromophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. Ethyl 2-(4-bromophenyl)-2,2-difluoroacetate

To a stirred solution of 1-bromo-4-iodobenzene (300 mg, 2.81 mmol) indimethyl sulfoxide (3 mL) was added ethyl 2-bromo-2,2-difluoroacetate(324 mg, 1.6 mmol) followed by copper powder (175 mg, 2.75 mmol) at roomtemperature and stirred at 55° C. for 6 h. The reaction mixture wasbasified with aqueous sodium bicarbonate solution and extracted withethyl acetate (3×10 mL). The combined organic layers were washed withwater (10 mL), brine (10 mL), dried over sodium sulfate, filtered andconcentrated. The obtained crude was purified by silica gel columnchromatography (20% ethyl acetate in pet ether) to afford ethyl2-(4-bromophenyl)-2,2-difluoroacetate (200 mg, 0.72 mmol, 25% yield) asa colorless liquid. GCMS (ESI) m/z 278.1 [M]⁺

B. 2-(4-Bromophenyl)-2,2-difluoroacetic acid

To a stirred solution of ethyl 2-(4-bromophenyl)-2,2-difluoroacetate(200 mg, 0.72 mmol) in mixture of tetrahydrofuran:methanol:water (15 mL,1:1:1) was added lithium hydroxide monohydrate (90 mg, 2.15 mmol) andstirred at room temperature for 4 h. The volatiles were removed underreduced pressure and obtained residue was dissolved in water (15 mL),washed with ethyl acetate (2×10 mL). Aqueous layer was acidified with 1Nhydrochloride aqueous solution and extracted with ethyl acetate (3×10mL). The combined organic layers were washed with brine (10 mL), driedover sodium sulfate, filtered and solvent was concentrated to afford2-(4-bromophenyl)-2,2-difluoroacetic acid (150 mg, 0.60 mmol, 84% yield)as semi-solid compound. MS (ESI) m/z 251.43 [M−H]⁺

C.2-(4-Bromophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To an ice cold solution of 2-(4-bromophenyl)-2,2-difluoroacetic acid(291 mg, 1.16 mmol) in pyridine (6 mL) was added phosphorus oxychloride(0.27 mL, 2.9 mmol) in dropwise and stirred at 0-5° C. for 1 h. Then,3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) was added into the reaction mixtureand stirred at room temperature for 2 h. The reaction mixture wasbasified with aqueous saturated sodium bicarbonate solution andextracted with ethyl acetate (3×15 mL). The combined organic layers werewashed with water (15 mL), brine (15 mL), dried over sodium sulfate,filtered and concentrated. The resultant residue was purified byReveleris C-18 reversed phase column chromatography (50-55% 0.1%acetonitrile in aqueous formic acid) to afford2-(4-bromophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(50 mg, 0.098 mmol, 10% yield) as white solid. MS (ESI) m/z 505.6[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.68 (t, J=5.8 Hz,1H), 7.77 (d, J=8.4 Hz, 2H), 7.68 (d, J=7.8 Hz, 1H), 7.54 (d, J=8.7 Hz,2H), 7.39 (s, 1H), 7.36 (d, J=8.1 Hz, 1H), 5.10 (dd, J=13.2, 4.8 Hz,1H), 4.45 (d, J=6.0 Hz, 2H), 4.43 (d, J=18.1 Hz, 1H), 4.28 (d, J=17.4Hz, 1H), 2.96-2.86 (m, 1H), 2.63-2.49 (m, 1H), 2.41-2.30 (m, 1H),2.07-1.94 (m, 1H).

Example 72N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2-methoxyethoxy)phenyl)acetamide

A. 1-Iodo-2-(2-methoxyethoxy)benzene

To a stirred solution of 2-iodophenol (1 g, 4.54 mmol) inN,N-dimethylformamide (10 mL) was added potassium carbonate (1.88 g,13.64 mmol) followed by potassium iodide (0.07 g, 0.45 mmol) and1-bromo-2-methoxyethane (0.46 mL, 4.99 mmol) at room temperature andstirred at 70° C. for 16 h. The reaction mixture was quenched with water(15 mL) and extracted with ethyl acetate (3×15 mL). The combined organiclayers were washed with water (15 mL), brine (15 mL), dried over sodiumsulfate, filtered and concentrated to afford 1-iodo-2-(2-methoxyethoxy)benzene (0.8 g, 2.87 mmol, 84% yield) as colorless liquid. GCMS(m/z) 278.1 [M⁺].

B. Ethyl 2,2-difluoro-2-(2-(2-methoxyethoxy)phenyl)acetate

To a stirred solution of 1-iodo-2-(2-methoxyethoxy)benzene (800 mg, 2.87mmol) in dimethyl sulfoxide (15 mL) was added ethyl2-bromo-2,2-difluoroacetate (0.42 mL, 4.31 mmol) followed by copperpowder (470 mg, 7.46 mmol) at RT and stirred at 60° C. for 6 h. Thereaction mixture was quenched with water and filtered through a Celitepad. The filtrate was basified with aqueous saturated sodium bicarbonatesolution and extracted with ethyl acetate (3×15 mL). The combinedorganic layers were washed with water (15 mL), brine (15 mL), dried oversodium sulfate, filtered and concentrated. The obtained crude waspurified by flash column chromatography (20% ethyl acetate in pet ether)to afford ethyl 2,2-difluoro-2-(2-(2-methoxyethoxy)phenyl)acetate (460mg, 1.37 mmol, 24% yield) as a colorless liquid. MS (ESI) m/z 274.2[M]⁺.

C. 2,2-Difluoro-2-(2-(2-methoxyethoxy)phenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(2-(2-methoxyethoxy)phenyl)acetate (450 mg, 1.64 mmol) intetrahydrofuran:methanol:water mixture (15 mL, 1:1:1) was added lithiumhydroxide monohydrate (206 mg, 4.92 mmol) and stirred at roomtemperature for 4 h. The volatiles were removed under reduced pressureand the obtained crude was dissolved in water (10 mL), washed with ethylacetate (2×10 mL). Aqueous layer was acidified with 1N hydrochlorideaqueous solution and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were washed with brine (10 mL), dried oversodium sulfate, filtered and concentrated to afford2,2-difluoro-2-(2-(2-methoxyethoxy)phenyl)acetic acid (290 mg, 1.17mmol, 72% yield) as semi-solid compound. MS (ESI) m/z 247.28 [M+H]⁺.

D.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2-methoxyethoxy)phenyl)acetamide

To an ice cold solution of2,2-difluoro-2-(2-(2-methoxyethoxy)phenyl)acetic acid (262 mg, 1.07mmol) in pyridine (9 mL) was added phosphorus oxychloride (0.27 mL, 2.9mmol) in dropwise and stirred at 0-5° C. for 1 h. Then, the reactionmixture was treated with3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) and stirred at room temperature for 2h. The reaction mixture was basified with aqueous saturated sodiumbicarbonate solution and extracted with ethyl acetate (3×15 mL). Thecombined organic layers were washed with water (15 mL), brine (15 mL),dried over sodium sulfate, filtered and solvent was concentrated. Theresultant residue was purified by Reveleris C-18 reversed phase columnchromatography (50-55% acetonitrile in 0.1% aqueous formic acid toaffordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2-methoxyethoxy)phenyl)acetamide(60 mg, 0.12 mmol, 12% yield) as white solid. MS (ESI) m/z 502.34[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.23 (t, J=5.6 Hz,1H), 7.71 (d, J=8.1 Hz, 1H), 7.55 (dd, J=9.6, 1.5 Hz, 1H), 7.52-7.48 (m,2H), 7.45 (d, J=8.1 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.07 (dd, J=7.8,7.2 Hz, 1H), 5.11 (dd, J=13.5, 5.1 Hz, 1H), 4.47 (d, J=6.3 Hz, 2H), 4.45(d, J=15.9 Hz, 1H), 4.31 (d, J=17.4 Hz, 1H), 4.05 (t, J=4.8 Hz, 2H),3.45 (t, J=5.1 Hz, 2H), 3.24 (s, 3H), 2.96-2.86 (m, 1H), 2.66-2.57 (m,1H), 2.45-2.30 (m, 1H), 2.04-1.94 (m, 1H).

Example 73N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-hydroxycyclohexyl)acetamide

A.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-hydroxycyclohexyl)acetamide

3-(5-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Mesylicacid (0.050 g, 0.135 mmol) (0.050 g, 0.113 mmol) was placed in a vialwith 2,2-difluoro-2-(1-hydroxycyclohexyl)acetic acid (0.026 g, 0.135mmol), diisopropylethylamine (0.071 mL, 0.406 mmol),1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol) andN,N-dimethylformamide (1.0 mL). The reaction mixture was stirred at 40°C. for 18 h. The reaction mixture was taken up in dimethylsulfoxide andpurified using reverse-phase semi preparatory HPLC (5-100%acetonitrile+0.1% formic acid in water+0.1% formic acid, over 20 min).Fractions containing desired product were combined and volatile organicswere removed under reduced pressure to giveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-hydroxycyclohexyl)acetamide(0.041 g, 0.091 mmol, 67.4% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.97 (s, 1H), 9.04 (t, J=6.15 Hz, 1H), 7.68 (d, J=7.88 Hz,1H), 7.50 (s, 1H), 7.43 (d, J=7.88 Hz, 1H), 5.19 (s, 1H), 5.10 (dd,J=5.04, 13.24 Hz, 1H), 4.40-4.47 (m, 3H), 4.27-4.34 (m, 1H), 2.86-2.96(m, 1H), 2.57-2.63 (m, 1H), 2.40 (qd, J=4.57, 13.19 Hz, 1H), 2.00 (dtd,J=2.05, 5.28, 12.61 Hz, 1H), 1.70 (d, J=12.30 Hz, 2H), 1.45-1.61 (m,5H), 1.34-1.43 (m, 2H), 1.00-1.13 (m, 1H). MS (ESI) m/z 450.2 [M+1]⁺.

Example 74N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-hydroxycyclopentyl)acetamide

A.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-hydroxycyclopentyl)acetamide

3-(5-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Mesylicacid (0.050 g, 0.135 mmol) (0.050 g, 0.113 mmol) was placed in a vialwith 2,2-difluoro-2-(1-hydroxycyclopentyl)acetic acid (0.024 g, 0.135mmol), diisopropylethylamine (0.071 mL, 0.406 mmol),1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.057 g, 0.149 mmol) andN,N-Dimethylformamide (1.0 mL). The reaction mixture was stirred at 40°C. for 18 h. The reaction mixture was taken up in dimethylsulfoxide andpurified using reverse-phase semi preparatory HPLC (5-100%acetonitrile+0.1% formic acid in water+0.1% formic acid, over 20 min).Fractions containing desired product were combined and volatile organicswere removed under reduced pressure to giveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-hydroxycyclopentyl)acetamide(0.044 g, 0.101 mmol, 74.7% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.97 (s, 1H), 9.10 (t, J=6.15 Hz, 1H), 7.68 (d, J=7.57 Hz,1H), 7.49 (s, 1H), 7.43 (d, J=7.88 Hz, 1H), 5.35 (s, 1H), 5.10 (dd,J=5.20, 13.40 Hz, 1H), 4.40-4.49 (m, 3H), 4.27-4.33 (m, 1H), 2.91 (ddd,J=5.36, 13.79, 17.42 Hz, 1H), 2.57-2.63 (m, 1H), 2.39 (qd, J=4.57, 13.29Hz, 1H), 2.00 (dtd, J=2.36, 5.26, 12.65 Hz, 1H), 1.88-1.96 (m, 2H),1.62-1.76 (m, 4H), 1.52-1.60 (m, 2H). MS (ESI) m/z 436.2 [M+1]⁺.

Example 75N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-methyl-4-(trifluoromethoxy)phenyl)acetamide

A. 4-Iodo-2-methyl-1-(trifluoromethoxy)benzene

To a stirred solution of 4-bromo-2-methyl-1-(trifluoromethoxy)benzene (1g, 3.92 mmol) in 1,4-dioxane (10 mL) was added sodium iodide (1.17 g,7.84 mmol), copper iodide (37.3 mg, 0.19 mmol),trans-N,N′-dimethylcyclohexane-1,2-diamine (61.3 mg, 0.43 mmol) at roomtemperature and stirred at 110° C. for 16 h. The reaction mixture wasquenched with water (50 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layer was washed with water (2×50 mL), brine (50mL), dried over sodium sulphate and concentrated to afford4-iodo-2-methyl-1-(trifluoromethoxy)benzene (1.0 g, 3.31 mmol, 84%) asbrown liquid. GCMS (m/z) 302[M⁺].

B. Ethyl 2,2-difluoro-2-(3-methyl-4-(trifluoromethoxy)phenyl)acetate

To a stirred solution of 4-iodo-2-methyl-1-(trifluoromethoxy)benzene(1.0 g, 3.31 mmol) in dimethylsulfoxide (10 mL) was reacted with ethyl2-bromo-2,2-difluoroacetate (802 mm, 3.97 mmol), copper (547 mg, 8.61mmol) and stirred at 55° C. for 6 h. The reaction mixture wasneutralized with aqueous saturated ammonium chloride solution andextracted with ethyl acetate (3×50 mL). The combined organic layer waswashed with water (2×50 mL), brine (50 mL) and dried over sodiumsulphate and was concentrated to afford ethyl2,2-difluoro-2-(3-methyl-4-(trifluoromethoxy)phenyl)acetate (700 mg,2.35 mmol, 70%) as a brown liquid. GCMS (m/z) 298.1[M]⁺.

C. 2,2-Difluoro-2-(3-methyl-4-(trifluoromethoxy)phenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(3-methyl-4-(trifluoromethoxy)phenyl)acetate (700 mg,2.35 mmol) in ethanol:tetrahydrofuran:water (15 mL, 1:1:1) was addedlithium hydroxide (296 mg, 7.05 mmol) and stirred at room temperaturefor 4 h. The reaction mixture was concentrated and the residue wasneutralized with saturated potassium bisulphate (20 mL) and extractedwith ethyl acetate (2×25 mL). The combined organic layer was washed withbrine (25 mL), dried over sodium sulphate and concentrated to afford2,2-difluoro-2-(3-methyl-4-(trifluoromethoxy)phenyl)acetic acid (400 mg,1.48 mmol, 63% yield). MS (ESI) m/z 269.45 [M−1]⁺.

D.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-methyl-4-(trifluoromethoxy)phenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(3-methyl-4-(trifluoromethoxy)phenyl) acetic acid (200mg, 0.74 mmol) in pyridine (20 mL) was added phosphoryl chloride (340mg, 2.22 mmol) dropwise and stirred at 0-5° C. for 1 h and then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (229 mg, 0.74 mmol) and stirred at room temperature for 30min. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layer was washed with water (2×50 mL), brine (50 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase column chromatography using40-50% acetonitrile in aqueous formic acid (0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-methyl-4-(trifluoromethoxy)phenyl)acetamide(80 mg, 0.15 mmol, 20% yield) as a white solid. MS (ESI) m/z 526.26[M+1]⁺. ¹H NMR (400 MHz, DMS)-d₆) 6=10.98 (s, 1H), 9.68 (t, J=6.1 Hz,1H), 7.68 (d, J=7.9 Hz, 1H), 7.62 (s, 1H), 7.57-7.47 (m, 2H), 7.42 (s,1H), 7.37 (d, J=7.9 Hz, 1H), 5.10 (dd, J=5.2, 13.4 Hz, 1H), 4.49-4.25(m, 4H), 2.98-2.85 (m, 1H), 2.69-2.55 (m, 1H), 2.44-2.34 (m, 1H), 2.33(s, 3H), 2.05-1.94 (m, 1H).

Example 76N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(3-ethoxypyridin-2-yl)-2,2-difluoroacetamide

A. 3-Ethoxy-2-iodopyridine

To a stirred solution of 2-iodopyridin-3-ol (1 g, 4.52 mmol) inN,N-dimethyl formamide (20 mL) was added potassium carbonate (0.936 g,6.78 mmol) at room temperature, and stirred for 10 min. To this reactionmixture was added ethyl iodide (1.41 g, 9.04 mmol) at room temperatureand stirred for 2 h at 80° C. The reaction mixture was quenched withwater (50 mL) and extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with water (2×100 mL), brine (100 mL), driedover sodium sulphate and concentrated. The resultant residue waspurified by column chromatography (silica-gel 100-200) 100% hexane aseluent to afford 3-ethoxy-2-iodopyridine (1 g, 4.0 mmol, 88.8% yield) asbrown liquid. LCMS (ESI) m/z 251.1 [M]⁺.

B. Ethyl 2-(3-ethoxypyridin-2-yl)-2,2-difluoroacetate

To a stirred solution of 3-ethoxy-2-iodopyridine (1.0 g, 4.01 mmol) indimethyl sulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate(1.6 mL, 8.03 mmol), copper (0.66 g, 10.44 mmol) and stirred at 55° C.for 16 h. The reaction mixture was neutralized with aqueous saturatedammonium chloride solution and extracted with ethyl acetate (3×100 mL).The combined organic layers were washed with water (2×100 mL), brine (10mL), dried over sodium sulphate and concentrated to afford ethyl2-(3-ethoxypyridin-2-yl)-2,2-difluoroacetate (800 mg, 3.26 mmol, 81%) asa brown liquid. LCMS (ESI) m/z 246.1[M]⁺.

C. 2-(3-Ethoxypyridin-2-yl)-2,2-difluoroacetic acid

To a cold (0° C.) stirred solution of ethyl2-(3-ethoxypyridin-2-yl)-2,2-difluoroacetate (800 mg, 3.26 mmol) in inMethanol:tetrahydrofuran:water (9 mL, 1:1:1) was added lithium hydroxidemonohydrate (410 mg, 9.78 mmol) and stirred at room temperature for 2 h.The reaction mixture was concentrated, the residue was neutralized with10% aqueous potassium bisulphate (10 mL) and extracted with ethylacetate (2×50 mL). The combined organic layers were washed with brine(20 mL), dried over sodium sulphate and concentrated to afford2-(3-ethoxypyridin-2-yl)-2,2-difluoroacetic acid (500 mg, 2.13 mmol, 88%yield) as a brown semi solid. The reaction mixture was taken to the nextstep without further purification.

D.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(3-ethoxypyridin-2-yl)-2,2-difluoroacetamide

To a cold (0° C.) stirred solution of2-(3-ethoxypyridin-2-yl)-2,2-difluoroacetic acid (252 mg, 1.16 mmol) inpyridine (20 mL) was added phosphoryl chloride (446.4 mg, 2.91 mmol)drop wise and stirred at 0-5° C. for 30 min. To this reaction mixturewas then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) and stirred at room temperature for 2h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×50 mL), brine (50 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase Grace column chromatographyusing 45-50% acetonitrile in aqueous formic acid (0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(3-ethoxypyridin-2-yl)-2,2-difluoroacetamide(60 mg, 0.12 mmol, 13% yield) as an off-white solid. LCMS (ESI) m/z473.29 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ=10.98 (s, 1H), 9.41 (br t,J=6.3 Hz, 1H), 8.22 (dd, J=1.1, 4.4 Hz, 1H), 7.72 (d, J=7.9 Hz, 1H),7.66-7.61 (m, 1H), 7.59-7.53 (m, 2H), 7.48 (d, J=7.9 Hz, 1H), 5.12 (dd,J=5.6, 13.2 Hz, 1H), 4.53-4.27 (m, 4H), 4.08 (q, J=7.2, 2H), 2.99-2.86(m, 1H), 2.70-2.56 (m, 1H), 2.47-2.32 (m, 1H), 2.05-1.96 (m, 1H), 1.19(t, J=7.2 Hz, 3H).

Example 77N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-methylpyridin-2-yl)acetamide

A. Ethyl 2,2-difluoro-2-(3-methylpyridin-2-yl)acetate

To a stirred solution of 2-iodo-3-methylpyridine (0.7 g, 3.19 mmol) indimethyl sulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate(0.8 mL, 6.39 mmol), copper (0.52 g, 8.29 mmol) and stirred for 16 h at50° C. The reaction mixture was neutralized with aqueous saturatedammonium chloride solution and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with water (2×10 mL), brine (10mL) and dried over sodium sulphate and was concentrated to afford ethyl2,2-difluoro-2-(3-methylpyridin-2-yl)acetate (500 mg, 2.32 mmol, 73%) asa brown liquid. GCMS (m/z) 215.2.

B. 2,2-Difluoro-2-(3-methylpyridin-2-yl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(3-methylpyridin-2-yl)acetate (500 mg, 2.32 mmol) inmethanol/tetrahydrofuran/water mixture (9 mL, 1:1:1) was added lithiumhydroxide monohydrate (327 mg, 6.97 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous potassium bisulphate (10 mL)and extracted with ethyl acetate (2×30 mL). The combined organic layerswere washed with brine (10 mL), dried over sodium sulphate andconcentrated to afford 2,2-difluoro-2-(3-methylpyridin-2-yl)acetic acid(400 mg, 2.13 mmol, 88% yield) as a brown semi solid. MS (ESI) m/z188.31.

C.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-methylpyridin-2-yl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(3-methylpyridin-2-yl)acetic acid (300 mg, 1.60 mmol) inpyridine (20 mL) was added phosphoryl chloride (735 mg, 4.80 mmol)dropwise and stirred at 0-5° C. for 30 min. To the reaction mixture wasthen added 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (395 mg, 1.60 mmol) and stirred at room temperature for 2h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×50 mL), brine (50 mL)and dried over sodium sulphate and concentrated. The resultant residuewas purified by Reveleris C-18 reversed phase column chromatographyusing 45-50% acetonitrile in aqueous formic acid (0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-methylpyridin-2-yl)acetamide(40 mg, 0.09 mmol, 7% yield) as an off-white solid. MS (ESI) m/z 443.30[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.45 (br t, J=6.1 Hz,1H), 8.51 (br d, J=3.9 Hz, 1H), 7.84 (br d, J=7.8 Hz, 1H), 7.72 (d,J=7.8 Hz, 1H), 7.63 (s, 1H), 7.51 (br d, J=7.8 Hz, 2H), 5.19-5.03 (m,1H), 4.58-4.28 (m, 4H), 2.92-2.85 (m, 1H), 2.68-2.54 (m, 1H), 2.45-2.30(m, 4H), 2.10-1.92 (m, 1H).

Example 78N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-methylpyridin-2-yl)acetamide

A. 2-Iodo-5-methylpyridine

To a stirred solution of 2-bromo-5-methylpyridine (2 g, 11.63 mmol) in1,4-dioxane (30 mL) was added sodium iodide (3.4 g, 23.24 mmol), copperiodide (110 mg, 0.58 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine(180 mg, 1.26 mmol) at room temperature and stirred at 110° C. for 16 hin sealed tube. The reaction mixture was quenched with water (30 mL) andextracted with ethyl acetate (3×30 mL). The combined organic layers werewashed with water (2×20 mL), brine (20 mL), dried over sodium sulphateand concentrated to afford 2-iodo-5-methylpyridine (1.3 g, 5.93 mmol,52% yield) as brown liquid. ¹H NMR (300 MHz, CDCl₃) δ 8.2 (s, 1H),7.6-7.56 (d, J=8.1 Hz, 1H), 7.18-7.12 (m, 1H), 2.3-2.25 (s, 1H).

B. Ethyl 2,2-difluoro-2-(5-methylpyridin-2-yl)acetate

To a stirred solution of 2-iodo-5-methylpyridine (1 g, 4.56 mmol) indimethyl sulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate(1.2 mL, 9.13 mmol), copper (0.75 g, 11.85 mmol) and stirred for 16 h at50° C. The reaction mixture was neutralized with aqueous saturatedammonium chloride solution and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with water (2×10 mL), brine (10mL), dried over sodium sulphate and concentrated to afford ethyl ethyl2,2-difluoro-2-(5-methylpyridin-2-yl)acetate (600 mg, 2.72 mmol, 60%) asa brown liquid. GCMS (m/z) 215.0

C. 2,2-Difluoro-2-(5-methylpyridin-2-yl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(5-methylpyridin-2-yl)acetate (500 mg, 2.32 mmol) in inmethanol/tetrahydrofuran/water mixture (9 mL, 1:1:1) was added lithiumhydroxide monohydrate (327 mg, 6.97 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous potassium bisulphate (10 mL)and extracted with ethyl acetate (2×30 mL). The combined organic layerswere washed with brine (10 mL), dried over sodium sulphate andconcentrated to afford 2,2-difluoro-2-(5-methylpyridin-2-yl)acetic acid(350 mg, 1.87 mmol, 87% yield) as a brown semi solid. MS (ESI) m/z188.39.

D.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-methylpyridin-2-yl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(5-methylpyridin-2-yl)acetic acid (180 mg, 0.97 mmol) inpyridine (20 mL) was added phosphoryl chloride (0.2 mL, 2.91 mmol)dropwise and stirred at 0-5° C. for 30 min. To this reaction mixture wasthen added 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) and stirred at room temperature for 2h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×50 mL), brine (50 mL)and dried over sodium sulphate and concentrated. The resultant residuewas purified by Reveleris C-18 reversed phase column chromatographyusing 45-50% acetonitrile in aqueous formic acid (0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-methylpyridin-2-yl)acetamide(64 mg, 0.14 mmol, 13% yield) as an off-white solid. MS (ESI) m/z 443.30[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.60 (br t, J=5.9 Hz,1H), 8.55 (bs, 1H), 7.88-7.98 (m, 1H), 7.69-7.63 (t, J=8.6 Hz, 2H), 7.52(s, 1H), 7.49-7.40 (m, 1H), 5.11 (dd, J=5.1, 13.5 Hz, 1H), 4.59-4.21 (m,4H), 2.98-2.85 (m, 1H), 2.68-2.53 (m, 1H), 2.45-2.39 (m, 4H), 2.06-1.97(m, 1H).

Example 79N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-6-fluorophenyl)-2,2-difluoroacetamide

A. 1-Ethoxy-3-fluoro-2-iodobenzene

To a stirred solution of 2-bromo-1-ethoxy-3-fluorobenzene (1 g, 4.58mmol) in 1,4-dioxane (30 mL) was added sodium iodide (1.37 g, 9.17mmol), copper iodide (43.6 mg, 0.22 mmol),trans-N,N′-dimethylcyclohexane-1,2-diamine (71.2 mg, 0.504 mmol) at roomtemperature and stirred at 110° C. for 16 h in sealed tube. The reactionmixture was quenched with water (100 mL) and extracted with ethylacetate (3×100 mL). The combined organic layers were washed with water(2×50 mL), brine (50 mL), dried over sodium sulphate and concentrated toafford 1-ethoxy-3-fluoro-2-iodobenzene (1 g, 5.93 mmol, 52% yield) asbrown liquid. GC-MS (ESI) m/z 266.

B. Ethyl 2-(2-ethoxy-6-fluorophenyl)-2,2-difluoroacetate

To a stirred solution of 1-ethoxy-3-fluoro-2-iodobenzene (1 g, 3.17mmol) in dimethyl sulfoxide (20 mL) was added ethyl2-bromo-2,2-difluoroacetate (1.53 g, 7.54 mmol), copper (0.62 g, 9.80mmol) and stirred for 16 h at 50° C. The reaction mixture wasneutralized with aqueous saturated ammonium chloride solution andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×20 mL), brine (20 mL), dried over sodium sulphateand concentrated to afford ethyl2-(2-ethoxy-6-fluorophenyl)-2,2-difluoroacetate (800 mg, 3.05 mmol, 81%)as a brown liquid. GC-MS (ESI) m/z 262.2

C. 2-(2-Ethoxy-6-fluorophenyl)-2,2-difluoroacetic acid

To a cold (0° C.) stirred solution of and was concentrated to give ethyl2-(2-ethoxy-6-fluorophenyl)-2,2-difluoroacetate (500 mg, 2.32 mmol) inin ethanol/tetrahydrofuran/water mixture (9 mL, 1:1:1) was added lithiumhydroxide monohydrate (327 mg, 6.97 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous potassium bisulphate (10 mL)and extracted with ethyl acetate (2×30 mL). The combined organic layerswere washed with brine (10 mL), dried over sodium sulphate andconcentrated to afford 2-(2-Ethoxy-6-fluorophenyl)-2,2-difluoroaceticacid (400 mg, 1.70 mmol, 56% yield) as a brown semi solid. LCMS (ESI)m/z 233.4 [M−1]⁻.

D.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-methylpyridin-2-yl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(5-methylpyridin-2-yl)acetic acid (272 mg, 1.16 mmol) inpyridine (20 mL) was added phosphoryl chloride (0.3 mL, 2.91 mmol)dropwise and stirred at 0-5° C. for 30 min. To this reaction mixture wasthen added 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) and stirred at room temperature for 2h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×50 mL), brine (50 mL)and dried over sodium sulphate and concentrated. The resultant residuewas purified by Reveleris C-18 reversed phase Grace columnchromatography using 45-50% acetonitrile in aqueous formic acid (0.1%)to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-methylpyridin-2-yl)acetamide(60 mg, 0.12 mmol, 12% yield) as an off-white solid. LCMS (ESI) m/z490.3 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ=10.98 (s, 1H), 9.36 (br t,J=6.1 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.54-7.47 (m, 3H), 7.45 (d, J=7.6Hz, 1H), 7.00-6.84 (m, 1H), 5.11 (br dd, J=5.0, 13.3 Hz, 1H), 4.52-4.27(m, 4H), 3.99 (q, J=7.0 Hz, 1H), 3.04-2.82 (m, 1H), 2.71-2.54 (m, 1H),2.46-2.28 (m, 1H), 2.04-1.94 (m, 1H), 1.14 (t, J=7.0 Hz, 1H).

Example 80N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4′-fluorobiphenyl-4-yl)acetamide

A. 1-(4′-Fluorobiphenyl-4-yl)ethanone

To a solution of 1-(4-bromophenyl)ethanone (2 g, 10.05 mmol) intoluene/ethanol ((10 mL, 2:1) was added 4-fluorophenylboronic acid (1.68g, 12.06 mmol) followed by potassium carbonate (3.46 g, 25.12 mmol) anddegassed for 10 min. The reaction mixture was further charged withtetrakis(triphenylphosphine)palladium(0) (1.16 mg, 1.005 mmol) anddegassed for additional 10 min and heated at 80° C. in a sealed tube for6 h. The reaction mixture was cooled to room temperature, filteredthrough the celite pad. The filtrate was diluted with cold water andextracted with ethyl acetate (3×10 mL). The combined organic layers werewashed with water (10 mL), brine (10 mL), dried over sodium sulfate,filtered and concentrated. The obtained residue was purified by columnchromatography (100-200 silica gel, 30% ethyl acetate in hexane) toafford 1-(4′-fluorobiphenyl-4-yl)ethanone (1 g, 4.67 mmol, 48% yield) asan off-white solid. MS (ESI) m/z 215.27 [M+1]⁺.

B. Ethyl 2-(4′-fluorobiphenyl-4-yl)-2-oxoacetate

To a stirred solution of 1-(4′-fluorobiphenyl-4-yl)ethanone (1.5 g,7.009 mmol) in pyridine (10 mL) was added selenium dioxide (1.94 g,17.52 mmol) at room temperature. The reaction mixture was stirred at100° C. for 16 h. The reaction mixture was filtered through celite padand washed with dichloromethane (15 mL). Ethyl chloroformate (15 mL) wasadded to the filtrate at 0° C. and stirred at room temperature for 4 h.The reaction mixture was quenched with ice water and extracted withdichloromethane (3×10 mL). The combined organic layers were washed with1N hydrochloride (15 mL), brine (10 mL), dried over sodium sulfate,filtered and concentrated to afford ethyl2-(4′-fluorobiphenyl-4-yl)-2-oxoacetate (900 mg, 3.308 mmol, 47% yield)as a colorless liquid. MS (ESI) m/z 273.51 [M+1]⁺.

C. Ethyl 2,2-difluoro-2-(4′-fluorobiphenyl-4-yl)acetate

Ethyl 2-(4′-fluorobiphenyl-4-yl)-2-oxoacetate (1 g, 3.676 mmol) wasadded in portion into diethylaminosulfur trifluoride (1.4 mL) at 0° C.and stirred at room temperature for 16 h. The reaction mixture wasquenched with aqueous sodium bicarbonate and extracted with ethylacetate (3×10 mL). The combined organic layers were washed with brine(10 mL), dried over sodium sulfate, filtered and concentrated. Theobtained crude was purified by column chromatography [using (100-200)silica gel, 10% ethyl acetate in pet ether] to afford ethyl2,2-difluoro-2-(4′-fluorobiphenyl-4-yl)acetate (800 mg, 2.72 mmol, 80%yield) as a colorless liquid. GCMS (ESI) m/z 294 [M+1]⁺.

D. 2,2-Difluoro-2-(4′-fluorobiphenyl-4-yl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(4′-fluorobiphenyl-4-yl)acetate (900 mg, 3.06 mmol) intetrahydrofuran:methanol:water mixture (12 mL, 1:1:1) was added lithiumhydroxide monohydrate (385 mg, 9.18 mmol) and stirred at roomtemperature for 4 h. The reaction mixture was concentrated under reducedpressure and the residue obtained was dissolved in water (10 mL), washedwith ethyl acetate (2×10 mL). The aqueous layer was acidified with 1Nhydrochloride aqueous solution and extracted with ethyl acetate (3×10mL). The combined organic layers were washed with brine (10 mL), driedover sodium sulfate, filtered and concentrated to afford2,2-difluoro-2-(4′-fluorobiphenyl-4-yl)acetic acid (400 mg, 2.91 mmol,44% yield) as semi-solid compound. The crude was used to next stepwithout purification.

E.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4′-fluorobiphenyl-4-yl)acetamide

To an ice cold solution of 2,2-difluoro-2-(4′-fluorobiphenyl-4-yl)aceticacid (266 mg, 1.16 mmol) in pyridine (15 mL) was added phosphorusoxychloride (445 mL, 2.91 mmol) drop wise and stirred at 0-5° C. for 1h. Then, 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) was added into the reaction mixtureand stirred at room temperature for 1 h. The reaction mixture wasbasified with aqueous saturated sodium bicarbonate solution andextracted with ethyl acetate (3×15 mL). The combined organic layers werewashed with brine (15 mL), dried over sodium sulfate, filtered andconcentrated. The resultant residue was purified by Reveleris C-18reversed phase column chromatography (50-55% acetonitrile in 0.1%aqueous formic acid) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4′-fluorobiphenyl-4-yl)acetamide (60 mg, 0.114 mmol, 11% yield) as white solid. MS (ESI) m/z522.46 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.98 (s, 1H), 9.68 (t,J=5.8 Hz, 1H), 7.86-7.72 (m, 4H), 7.72-7.62 (m, 3H), 7.43-7.28 (m, 4H),5.09 (dd, J=13.2, 5.1 Hz, 1H), 4.47 (d, J=5.7 Hz, 2H), 4.38 (d, J=17.1Hz, 1H), 4.24 (d, J=17.1 Hz, 1H), 3.00-2.81 (m, 1H), 2.64-2.53 (m, 1H),2.38-2.20 (m, 1H), 2.03-1.90 (m, 1H).

Example 81N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-5-fluorophenyl)-2,2-difluoroacetamide

A. 1-(2-Ethoxy-5-fluorophenyl)ethanone

To a stirred solution of 1-(5-fluoro-2-hydroxyphenyl)ethanone (500 mg,3.24 mmol) in N,N-dimethylformamide (15 mL) was added ethyl bromide (607mg, 3.89 mmol) followed by potassium carbonate (1.11 g, 8.10 mmol) andstirred at 90° C. for 16 h. The reaction mixture was diluted with icewater (15 mL) and extracted with ethyl acetate (3×10 mL). The combinedorganic layers were washed with water (10 mL), brine (10 mL), dried oversodium sulfate, filtered and concentrated to afford1-(2-ethoxy-5-fluorophenyl)ethanone (350 mg, 1.36 mmol, 20% yield) as acolorless liquid. MS (ESI) m/z 183.34 [M+1]⁺.

B. Ethyl 2-(2-ethoxy-5-fluorophenyl)-2-oxoacetate

To a stirred solution of 1-(2-ethoxy-5-fluorophenyl)ethanone (2 g, 10.99mmol) in pyridine (10 mL) was added selenium dioxide (3.05 g, 27.47mmol) at room temperature heated at 100° C. for 16 h. The reactionmixture was filtered through a Celite pad and washed withdichloromethane (15 mL). 4 mL of ethyl chloroformate was added to thefiltrate at 0° C. and stirred at room temperature for 4 h. The reactionmixture was quenched with ice water and extracted with dichloromethane(3×30 mL). The combined organic layers were washed with 1N hydrochloridesolution (30 mL), brine (30 mL), dried over sodium sulfate, filtered andconcentrated to afford ethyl 2-(2-ethoxy-5-fluorophenyl)-2-oxoacetate(1.7 g, 7.08 mmol, 75% yield) as a colorless liquid. Without furtherpurification used for next step.

C. Ethyl 2-(2-ethoxy-5-fluorophenyl)-2,2-difluoroacetate

Ethyl 2-(2-ethoxy-5-fluorophenyl)-2-oxoacetate (1 g, 4.16 mmol) wasadded into diethylamino sulfur trifluoride (2 mL) at 0° C. and stirredat room temperature for 16 h. The reaction mixture was quenched withaqueous sodium bicarbonate solution and extracted with ethyl acetate(3×10 mL). The combined organic layers were washed with brine (10 mL),dried over sodium sulfate, filtered and concentrated. Obtained crude waspurified by column chromatography (100-200 silica gel, 10% ethyl acetatein pet ether) to afford ethyl2-(2-ethoxy-5-fluorophenyl)-2,2-difluoroacetate (800 mg, 3.05 mmol, 73%yield) as a colourless liquid. MS (ESI) m/z 262.2 [M]⁺.

D. 2-(2-Ethoxy-5-fluorophenyl)-2,2-difluoroacetic acid

To a stirred solution of ethyl2-(2-ethoxy-5-fluorophenyl)-2,2-difluoroacetate (600 mg, 2.29 mmol) inmixture of tetrahydrofuran:methanol:water (12 mL, 1:1:1) was addedlithium hydroxide monohydrate (288 mg, 6.87 mmol) and stirred at roomtemperature for 16 h. The volatiles were removed under reduced pressureand obtained residue was dissolved in water (10 mL) and washed withethyl acetate (2×10 mL). Aqueous layer was acidified with 1Nhydrochloride aqueous solution and extracted with ethyl acetate (3×10mL). The combined organic layers were washed with brine (10 mL), driedover sodium sulfate, filtered and solvent was concentrated to afford2-(2-ethoxy-5-fluorophenyl)-2,2-difluoroacetic acid (310 mg, 1.32 mmol,87% yield) as semi-solid compound. ¹H NMR (400 MHz, CDCl₃) δ 7.38 (dd,J=8.8, 3.2 Hz, 1H), 7.16 (ddd, J=11.2, 8.8, 3.2 Hz, 1H), 6.91 (dd,J=9.2, 4.4 Hz, 1H), 4.08 (q, J=7.2 Hz, 2H), 2.68 (brs, 1H), 1.39 (t,J=6.8 Hz, 3H).

E.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-5-fluorophenyl)-2,2-difluoroacetamide

To an ice cold solution of2-(2-ethoxy-5-fluorophenyl)-2,2-difluoroacetic acid (151 mg, 0.65 mmol)in pyridine (9 mL) was added phosphorus oxychloride (0.18 mL, 1.94 mmol)in drop wise and stirred at 0-5° C. for 1 h. Then,3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (200 mg, 0.65 mmol) was added into the reaction mixtureand stirred at room temperature for 1 h. The reaction mixture wasbasified with aqueous saturated sodium bicarbonate solution andextracted with ethyl acetate (3×15 mL). The combined organic layers werewashed with brine (15 mL), dried over sodium sulfate, filtered andconcentrated. The resultant residue was purified by Reveleris C-18reversed phase column chromatography (50-55% acetonitrile in 0.1%aqueous formic acid) to giveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-5-fluorophenyl)-2,2-difluoroacetamide (55 mg, 0.11 mmol, 17% yield) as white solid. MS (ESI) m/z490.1 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.38 (t, J=5.6Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J=8.4 Hz, 1H),7.39-7.34 (m, 2H), 7.19-7.11 (m, 1H), 5.11 (dd, J=13.2, 5.1 Hz, 1H),4.47 (d, J=6.6 Hz, 2H), 4.45 (d, J=16.5 Hz, 1H), 4.31 (d, J=17.7, 1H),3.97 (q, J=6.9 Hz, 2H), 2.96-2.85 (m, 1H), 2.67-2.55 (m, 1H), 2.45-2.30(m, 1H), 2.04-1.94 (m, 1H), 1.11 (t, J=7.2 Hz, 3H).

Example 822-Cyclopentyl-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. Ethyl 2,2-difluoro-2-(1-hydroxycyclopentyl)acetate

To a stirred solution of cyclopentanone (1 g, 11.90 mmol) intetrahydrofuran (20 mL) was added anhydrous cerium(III) chloride (0.06g, 0.24 mmol) followed by activated zinc dust (0.93 g, 14.28 mmol) andethyl 2-bromo-2,2-difluoroacetate (2.01 mL, 15.47 mmol) at 0° C. andstirred at room temperature for 16 h. The reaction mixture was dilutedwith water (20 mL) and extracted with ethyl acetate (3×20 mL). Thecombined organic layers were washed with water (20 mL), brine (20 mL),dried over sodium sulfate, filtered and solvent was concentrated andobtained crude was purified by silica gel column chromatography (30%ethyl acetate in pet ether) to afford ethyl2,2-difluoro-2-(1-hydroxycyclopentyl)acetate (0.55 g, 2.40 mmol, 22%yield) as a colorless liquid. ¹H NMR (300 MHz, DMSO-d₆) δ 5.48 (s, 1H),4.27 (q, J=6.9 Hz, 2H), 1.87-1.81 (m, 2H), 1.75-1.57 (m, 6H), 1.26 (t,J=6.9 Hz, 3H).

B. Ethyl 2-cyclopentenyl-2,2-difluoroacetate

To a stirred solution of ethyl2,2-difluoro-2-(1-hydroxycyclopentyl)acetate (50 mg, 0.24 mmol) inpyridine (1.7 mL) was added thionyl chloride (0.17 mL, 2.40 mmol) at 0°C. and stirred at room temperature for 16 h. The reaction mixture wasdiluted with water (4 mL) and basified with aqueous sodium bicarbonatesolution and extracted with ethyl acetate (3×4 mL). The combined organiclayers were washed with water (4 mL), brine (4 mL), dried over sodiumsulfate, filtered and concentrated. The obtained crude product waspurified by silica gel column chromatography (30% ethyl acetate in petether) to afford ethyl 2-cyclopentenyl-2,2-difluoroacetate (25 mg, 0.13mmol, 45% yield) as a colorless liquid. MS (ESI) m/z 190.1 [M]⁺.

C. Ethyl 2-cyclopentyl-2,2-difluoroacetate

To a stirred solution of ethyl 2-cyclopentenyl-2,2-difluoroacetate (100mg, 0.52 mmol) in ethyl acetate (10 mL) was added slurry of 10%palladium hydroxide (30 mg) in ethyl acetate under nitrogen stream andstirred under hydrogen balloon pressure at room temperature for 4 h. Thehydrogen atmosphere was evacuated and reaction mixture was filteredthrough a Celite pad, filtrate was concentrated to afford ethyl2-cyclopentyl-2,2-difluoroacetate (60 mg, 0.31 mmol, 59% yield) as acolorless liquid. ¹H NMR (300 MHz, CDCl₃) δ 4.32 (q, J=7.2 Hz, 2H),2.67-2.57 (m, 1H), 1.79-1.55 (m, 8H), 1.35 (t, J=6.9 Hz, 3H).

D. 2-Cyclopentyl-2,2-difluoroacetic acid

To a stirred solution of ethyl 2-cyclopentyl-2,2-difluoroacetate (450mg, 2.34 mmol) in tetrahydrofuran:methanol:water mixture (15 mL, 1:1:1)was added lithium hydroxide monohydrate (295 mg, 7.03 mmol) and stirredat room temperature for 4 h. The volatiles were removed under reducedpressure and the resultant residue was dissolved in water (10 mL) andwashed with ethyl acetate (2×10 mL). Aqueous layer was acidified with 1Nhydrochloride aqueous solution and extracted with ethyl acetate (3×10mL). The combined organic layers were washed with brine (10 mL), driedover sodium sulfate, filtered and concentrated to afford2-cyclopentyl-2,2-difluoroacetic acid (280 mg, 1.70 mmol, 72% yield) assemi-solid compound. ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (brs, 1H),2.69-2.59 (m, 1H), 1.84-1.59 (m, 8H).

E.2-Cyclopentyl-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To an ice cold solution of 2-cyclopentyl-2,2-difluoroacetic acid (159mg, 0.97 mmol) in pyridine (9 mL) was added phosphorus oxychloride (0.27mL, 2.9 mmol) drop wise and stirred at 0-5° C. for 1 h. Then,3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) was added into the reaction mixtureand stirred at room temperature for 2 h. The reaction mixture wasbasified with aqueous saturated sodium bicarbonate solution andextracted with ethyl acetate (3×15 mL). The combined organic layers werewashed with brine (15 mL), dried over sodium sulfate, filtered andconcentrated. The resultant residue was purified by Reveleris C-18reversed phase column chromatography (50-55% acetonitrile in 0.1%aqueous formic acid) to afford2-cyclopentyl-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(50 mg, 0.12 mmol, 12% yield) as white solid. MS (ESI) m/z 420.17[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.36 (t, J=6.3 Hz,1H), 7.70 (d, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.40 (d, J=8.1 Hz, 1H), 5.11(dd, J=13.5, 5.1 Hz, 1H), 4.46 (d, J=17.1 Hz, 1H), 4.44 (d, J=6.0 Hz,2H), 4.31 (d, J=17.7 Hz, 1H), 2.92-2.87 (m, 1H), 2.73-2.57 (m, 2H),2.40-2.36 (m, 1H), 2.02-1.98 (m, 1H), 1.70-1.53 (m, 8H).

Example 83N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-methyl-4-(trifluoromethoxy)phenyl)acetamide

A. 2-Chloro-4-iodo-1-(trifluoromethoxy)benzene

To a cold (0° C.) stirred solution of3-chloro-4-(trifluoromethoxy)aniline (2.5 g, 11.79 mmol) in aq H₂SO₄ (10mL) was added sodium nitrite (894 mg, 12.96 mmol) urea (106 mg, 1.768mmol) and potassium iodide (4.1 g, 24.75 mmol) at 0° C. and stirred at50° C. for 2 h. The reaction mixture was quenched with aqueous sodiumbicarbonate solution (40 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with water (2×10 mL), brine (10mL), dried over sodium sulphate and concentrated to afford2-chloro-4-iodo-1-(trifluoromethoxy)benzene and crude (2 g, 6.23 mmol,52% yield) as colorless liquid which was used to next step without anypurification.

B. Ethyl 2-(3-chloro-4-(trifluoromethoxy)phenyl)-2,2-difluoroacetate

To a stirred solution of 2-chloro-4-iodo-1-(trifluoromethoxy)benzene(1.5 g, 4.56 mmol) in dimethylsulfoxide (12 mL) was reacted with ethyl2-bromo-2,2-difluoroacetate (138 g 6.84 mmol), copper (753 mg, 11.85mmol) and stirred for 6 h at 55° C. The reaction mixture was neutralizedwith aqueous saturated ammonium chloride solution and extracted withethyl acetate (3×50 mL). The combined organic layers were washed withwater (2×10 mL), brine (10 mL), dried over sodium sulphate andconcentrated to afford ethyl2-(3-chloro-4-(trifluoromethoxy)phenyl)-2,2-difluoroacetate (1.1 g, 3.45mmol, 78% yield) as a brown liquid. MS (ESI) m/z 318 [M+1]⁺.

C. 2-(3-Chloro-4-(trifluoromethoxy)phenyl)-2,2-difluoroacetic acid

To a cold (0° C.) stirred solution of ethyl2-(3-chloro-4-(trifluoromethoxy)phenyl)-2,2-difluoroacetate (2 g, 6.289mmol) in in methanol/tetrahydrofuran/water mixture (10 mL, 1:1:1) wasadded lithium hydroxide monohydrate (792 mg, 18.86 mmol) and stirred atroom temperature for 16 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous hydrochloric acid (10 mL) in1,4-dioxane and extracted with ethyl acetate (2×30 mL). The combinedorganic layers were washed with brine (10 mL), dried over sodiumsulphate and concentrated to afford2-(3-chloro-4-(trifluoromethoxy)phenyl)-2,2-difluoroacetic acid andcrude (800 mg, 2.75 mmol, 44% yield) as a brown semi solid which wasused to next step without any purification

D.2-(3-Chloro-4-(trifluoromethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a cold (0° C.) stirred solution of3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (250 mg, 0.809 mmol) and2-(3-chloro-4-(trifluoromethoxy)phenyl)-2,2-difluoroacetic acid (234 mg,0.970 mmol) in N,N-dimethylformamide (10 mL) was addedN,N-diisopropylethylamine (0.4 mL, 2.42 mmol) followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (614 mg, 1.61 mmol) and stirred at roomtemperature for 16 h. The reaction mixture was diluted with water (30mL) and extracted with ethyl acetate (2×40 mL). The combined organiclayers were washed with brine (20 mL), dried over sodium sulphate andconcentrated dried under vacuum. The product was purified by RevelerisC-18 reversed phase column using 60% acetonitrile in aqueous formic acid(0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2-hydroxyethoxy)phenyl)acetamide(35 mg, 0.064 mmol, 8% yield) as an off-white solid. MS (ESI) m/z 546.26[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆,) δ 10.98 (s, 1H), 9.75 (br t, J=5.9Hz, 1H), 7.92-7.90 (m, 1H), 7.82-7.64 (m, 3H), 7.47-7.34 (m, 2H), 5.10(dd, J=13.2, 5.1 Hz, 1H), 4.51-4.24 (m, 4H), 2.99-2.84 (m, 1H),2.67-2.55 (m, 1H), 2.45-2.25 (m, 1H), 2.05-1.93 (m, 1H).

Example 84N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamide

A. 1-Bromo-4-methoxy-2-(trifluoromethyl)benzene

To a stirred solution of 4-bromo-3-(trifluoromethyl)phenol (2 g, 8.29mmol) in N,N-dimethyl formamide (20 mL) was added portion wise sodiumhydride (398 mg, 16.59 mmol) at 0° C., and stirred for 30 min at roomtemperature. To this reaction mass was added methyl iodide (671 mg,10.78 mmol) at 0° C. and stirred at room temperature for 1 h. Thereaction mixture was quenched with water (50 mL) and extracted withethyl acetate (2×200 mL). The combined organic layers were washed withwater (2×100 mL), brine (100 mL), dried over sodium sulphate andconcentrated. The resultant residue was purified by columnchromatography (silica-gel 100-200) 100% hexane as a eluent to afford1-bromo-4-methoxy-2-(trifluoromethyl)benzene (1.2 g, 4.72 mmol, 57%yield) as an off-white solid. MS (ESI) m/z 254.1 [M]⁺.

B. 1-Iodo-4-methoxy-2-(trifluoromethyl)benzene

To a stirred solution of 1-bromo-4-methoxy-2-(trifluoromethyl)benzene (1g, 3.93 mmol) in 1,4-dioxane (10 mL) was added sodium iodide (1.76 g,11.79 mmol), copper iodide (150 mg, 0.786 mmol) followed bytrans-N,N′-dimethylcyclohexane-1,2-diamine (168 mg, 1.18 mmol) at roomtemperature and stirred at 110° C. for 2 h in microwave. The reactionmixture was quenched with water (20 mL) and extracted with ethyl acetate(3×200 mL). The combined organic layers were washed with water (2×50mL), brine (50 mL), dried over sodium sulphate and concentrated toafford 1-iodo-4-methoxy-2-(trifluoromethyl)benzene (800 g, 2.65 mmol,68% yield) as brown liquid. MS (ESI) m/z 302.0 [M]⁺.

C. Ethyl 2,2-difluoro-2-(4-methoxy-2-(trifluoromethyl)phenyl)acetate

To a stirred solution of 1-iodo-4-methoxy-2-(trifluoromethyl)benzene(800 mg, 2.65 mmol) in dimethyl sulfoxide (20 mL) was added ethyl2-iodo-2,2-difluoroacetate (0.62 mL, 3.97 mmol), copper (438 g, 6.89mmol) and stirred for 16 h at room temperature. The reaction mixture wasneutralized with aqueous saturated ammonium chloride solution andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×10 mL), brine (10 mL), dried over sodium sulphateand concentrated to afford ethyl2,2-difluoro-2-(4-methoxy-2-(trifluoromethyl)phenyl)acetate (600 mg,2.01 mmol, 76%) as a brown liquid. MS (ESI) m/z 298.1 [M]⁺.

D. 2,2-Difluoro-2-(4-methoxy-2-(trifluoromethyl)phenyl)acetic acid

To a cold (0° C.) stirred solution of ethyl 2,2-difluoro-2-(4-methoxy-2-(trifluoromethyl) phenyl) acetate (600 mg,2.01 mmol) in in methanol/tetrahydrofuran/water (9 mL, 1:1:1) was addedlithium hydroxide monohydrate (253 mg, 6.03 mmol) and stirred at roomtemperature for 4 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous potassium bisulphate (10 mL)and extracted with ethyl acetate (2×30 mL). The combined organic layerswere washed with brine (10 mL), dried over sodium sulphate andconcentrated to afford2,2-difluoro-2-(4-methoxy-2-(trifluoromethyl)phenyl)acetic acid (450 mg,1.66 mmol, 83% yield) as a brown semi solid. MS (ESI) m/z 269.30 [M−1]⁺.

E.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(4-methoxy-2-(trifluoromethyl)phenyl)acetic acid (314 mg,1.16 mmol) in pyridine (20 mL) was added phosphoryl chloride (0.7 mL,2.91 mmol) dropwise and stirred at 0-5° C. for 30 min. To this,3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) was added and stirred at roomtemperature for 1 h. The reaction mixture was neutralized with aqueoussaturated sodium bicarbonate (up to pH-8) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with water(2×50 mL), brine (50 mL), dried over sodium sulphate and concentrated.The resultant residue was purified by Reveleris C-18 reversed phasecolumn chromatography using 50-55% acetonitrile in aqueous formic acid(0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamide(35 mg, 0.07 mmol, 7% yield) as an off-white solid. MS (ESI) m/z 526.21[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.97 (br s, 1H), 9.59 (br t,J=5.87 Hz, 1H), 7.81-7.60 (m, 2H), 7.56-7.20 (m, 4H), 5.11 (br dd,J=13.39, 4.95 Hz, 1H), 4.56-4.14 (m, 4H), 3.89 (s, 3H), 3.02-2.85 (m,1H), 2.67-2.55 (m, 1H), 2.46-2.30 (m, 1H), 2.06-1.94 (m, 1H).

Example 85N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2-hydroxyethoxy)phenyl)acetamide

A. (2-Bromoethoxy)(tert-butyl)dimethylsilane

To a stirred solution of 2-bromoethanol (10 g, 80 mmol) indichloromethane (100 mL) was added tert-butylchlorodimethylsilane (14.5g, 96.77 mmol) and imidazole (10 g, 161.2 mmol) at 0° C. and stirred atroom temperature for 16 h. The reaction mixture was quenched withaqueous sodium bicarbonate solution (40 mL) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with water(2×10 mL), brine (10 mL), dried over sodium sulphate and concentrated toafford (2-bromoethoxy)(tert-butyl)dimethylsilane (8 g, 33.61 mmol, 42%yield) as colorless liquid.

B. Tert-butyl(2-(2-iodophenoxy)ethoxy)dimethylsilane

To a stirred solution of 2-iodophenol (3 g, 13.6 mmol) inN,N-dimethylformamide (20 mL) was added(2-bromoethoxy)(tert-butyl)dimethylsilane (3.89 g, 16.36 mmol),tert-butyl ammonium iodide (1 g 2.72 mmol) and potassium carbonate (4.69g 34 mmol) at 0° C. and stirred at 80° C. for 16 h. The reaction mixturewas quenched with water (40 mL) and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with water (2×10 mL), brine(10 mL), dried over sodium sulphate and concentrated to affordtert-butyl(2-(2-iodophenoxy)ethoxy)dimethylsilane (2.5 g, 6.613 mmol,49% yield) as colorless liquid.

C. Ethyl 2,2-difluoro-2-(2-(2-hydroxyethoxy)phenyl)acetate

To a stirred solution oftert-butyl(2-(2-iodophenoxy)ethoxy)dimethylsilane (3 g, 7.936 mmol) indimethyl sulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate(2.41 g 11.90 mmol), copper powder (1.3 g, 20.63 mmol) and stirred at50° C. for 6 h. The reaction mixture was neutralized with aqueoussaturated ammonium chloride solution and extracted with ethyl acetate(3×50 mL). The combined organic layers were washed with water (2×10 mL),brine (10 mL), dried over sodium sulphate and concentrated to affordethyl 2,2-difluoro-2-(2-(2-hydroxyethoxy)phenyl)acetate (900 mg, 3.406mmol, 45%) as a brown liquid.

D. 2,2-Difluoro-2-(2-(2-hydroxyethoxy)phenyl)acetic acid

To an ice cold solution of ethyl2,2-difluoro-2-(2-(2-hydroxyethoxy)phenyl)acetate (1.2 g, 3.20 mmol) inethanol/tetrahydrofuran/water mixture (15 mL, 1:1:1) was added lithiumhydroxide monohydrate (404 mg, 9.62 mmol) and stirred at roomtemperature for 6 h. The reaction mixture was concentrated and theresultant residue was neutralized with 10% aqueous hydrochloric acid in1,4-dioxane (10 mL) and extracted with ethyl acetate (2×30 mL). Thecombined organic layer was washed with brine (10 mL), dried over sodiumsulphate and concentrated to afford2,2-difluoro-2-(2-(2-hydroxyethoxy)phenyl)acetic acid (650 mg, 2.82mmol, 65% yield) as a brown semi solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.68(d, J=7.2 Hz, 1H), 7.46 (dd, J=8.1 Hz, 7.8 Hz, 1H), 7.09 (dd, J=8.0, 7.8Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.38 (brs, 1H), 4.12 (t, J=5.4 Hz, 2H),3.99 (t, J=3.9 Hz, 2H).

E.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2-hydroxyethoxy)phenyl)acetamide

To an ice cold solution of3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.970 mmol) and2,2-difluoro-2-(2-(2-hydroxyethoxy)phenyl)acetic acid (225 mg, 0.970mmol) in N,N-dimethylformamide (10 mL) was addedN,N-diisopropylethylamine (0.5 mL, 2.91 mmol) followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (737 mg, 1.94 mmol) and stirred at roomtemperature for 12 h. The reaction mixture was diluted with water (30mL) and extracted with ethyl acetate (2×40 mL). The combined organiclayers were washed with brine (20 mL), dried over sodium sulphate andconcentrated dried under vacuum. The product was purified by RevelerisC-18 reversed phase column (60% acetonitrile in 0.1% aqueous formicacid) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2-hydroxyethoxy)phenyl)acetamide (40 mg, 0.082 mmol, 8% yield) as an off-white solid. MS(ESI) m/z 488.12. ¹H NMR (300 MHz, DMSO-d₆): δ=10.98 (s, 1H), 9.29 (t,J=5.7 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.60-7.39 (m, 4H), 7.16 (br d,J=8.1 Hz, 1H), 7.10-7.01 (m, 1H), 5.11 (dd, J=13.0, 5.0 Hz, 1H), 4.72(t, J=5.5 Hz, 1H), 4.51-4.27 (m, 4H), 3.98 (t, J=5.3 Hz, 1H), 3.60 (q,J=5.3 Hz, 1H), 3.00-2.82 (m, 1H), 2.63-2.54 (m, 1H), 2.45-2.32 (m, 1H),2.06-1.94 (m, 1H).

Example 862-(4-Chloro-2-ethoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. 1-(4-Chloro-2-ethoxyphenyl)ethanone

To a stirred solution of 1-(4-chloro-2-hydroxyphenyl)ethanone (2 g,11.76 mmol) in N,N-dimethylformamide (15 mL) was added ethyl iodide (2.8mL, 29.4 mmol) followed by potassium carbonate (4.87 g, 35.29 mmol) andstirred at 90° C. for 16 h. The reaction mixture was diluted with icewater (20 mL) and extracted with ethyl acetate (3×20 mL). The combinedorganic layers were washed with water (20 mL), brine (20 mL), dried oversodium sulfate, filtered and concentrated to afford1-(4-chloro-2-ethoxyphenyl)ethanone (1.7 g, 8.58 mmol, 73% yield) as acolorless liquid. MS (ESI) m/z 199.41 [M+1]⁺.

B. Ethyl 2-(4-chloro-2-ethoxyphenyl)-2-oxoacetate

To a stirred solution of 1-(4-chloro-2-ethoxyphenyl)ethanone (1.7 g,8.58 mmol) in pyridine (10 mL) was added selenium dioxide (2.38 g, 21.46mmol) at room temperature and stirred at 100° C. for 16 h. The reactionmixture was filtered through a Celite pad and washed withdichloromethane (15 mL). Ethyl chloroformate (3.4 mL) was added to thefiltrate at 0° C. and stirred at room temperature for 4 h. The reactionmixture was quenched with ice water and extracted with dichloromethane(3×20 mL). The combined organic layers were washed with 1N hydrochloridesolution (20 mL), brine (20 mL), dried over sodium sulfate, filtered andconcentrated to afford ethyl 2-(4-chloro-2-ethoxyphenyl)-2-oxoacetate(1.2 g, 4.68 mmol, 54% yield) as a colorless liquid. MS (ESI) m/z 256.1[M]⁺.

C. Ethyl 2-(4-chloro-2-ethoxyphenyl)-2,2-difluoroacetate

Ethyl 2-(4-chloro-2-ethoxyphenyl)-2-oxoacetate (1 g, 3.9 mmol) was addedinto diethylamino sulfur trifluoride (1.89 g, 11.72 mmol) at 0° C. andstirred at room temperature for 16 h. The reaction mixture was quenchedwith aqueous sodium bicarbonate solution and extracted with ethylacetate (3×15 mL). The combined organic layers were washed with brine(15 mL), dried over sodium sulfate, filtered and concentrated. Obtainedcrude was purified by flash chromatography (100-200 silica gel, 10%ethyl acetate in pet ether) to afford ethyl2-(4-chloro-2-ethoxyphenyl)-2,2-difluoroacetate (570 mg, 2.05 mmol, 52%yield) as a colourless liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, J=8.4Hz, 1H), 7.03 (dd, J=8.4, 1.6 Hz, 1H), 6.91 (s, 1H), 4.31 (q, J=7.6 Hz,2H), 4.05 (q, J=6.8 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H), 1.31 (t, J=7.2 Hz,3H).

D. 2-(4-Chloro-2-ethoxyphenyl)-2,2-difluoroacetic acid

To a stirred solution of ethyl2-(4-chloro-2-ethoxyphenyl)-2,2-difluoroacetate (470 mg, 1.69 mmol) intetrahydrofuran:methanol:water (12 mL, 1:1:1) was added lithiumhydroxide monohydrate (213 mg, 5.07 mmol) and stirred at roomtemperature for 16 h. The volatiles were removed under reduced pressureand obtained crude was dissolved in water (10 mL) and washed with ethylacetate (2×10 mL). Aqueous layer was acidified with 1N hydrochlorideaqueous solution and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were washed with brine (10 mL), dried oversodium sulfate, filtered and solvent was concentrated to afford2-(4-chloro-2-ethoxyphenyl)-2,2-difluoroacetic acid (260 mg, 1.04 mmol,61% yield) as semi-solid compound. ¹H NMR (300 MHz, CDCl₃) δ 7.58 (d,J=8.7 Hz, 1H), 7.05 (d, J=8.1 Hz, 1H), 6.94 (s, 1H), 4.09 (q, J=7.2 Hz,2H), 1.39 (t, J=6.9 Hz, 3H).

E.2-(4-Chloro-2-ethoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To an ice cold solution of 2-(4chloro-2-ethoxyphenyl)-2,2-difluoroacetic acid (178 mg, 0.71 mmol) inpyridine (9 mL) was added phosphorus oxychloride (0.18 mL, 1.94 mmol) indrop wise and stirred at 0-5° C. for 1 h. Then,3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (200 mg, 0.64 mmol) was added into the reaction mixtureand stirred at room temperature for 1 h. The reaction mixture wasbasified with aqueous saturated sodium bicarbonate solution andextracted with ethyl acetate (3×15 mL). The combined organic layers werewashed with brine (15 mL), dried over sodium sulfate, filtered andconcentrated. The resultant residue was purified by Reveleris C-18reversed phase column chromatography (50-55% acetonitrile in 0.1%aqueous formic acid) to give2-(4-chloro-2-ethoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide (58 mg, 0.11 mmol, 18% yield) as white solid. MS (ESI) m/z 506.1[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.38 (t, J=5.6 Hz,1H), 7.71 (d, J=7.8 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.50 (s, 1H), 7.44(d, J=7.5 Hz, 1H), 7.22 (s, 1H), 7.12 (dd, J=7.8, 1.8 Hz, 1H), 5.11 (dd,J=13.2, 5.1 Hz, 1H), 4.46 (d, J=17.2 Hz, 1H), 4.46 (d, J=5.7 Hz, 2H),4.31 (d, J=17.4, 1H), 4.03 (q, J=6.9 Hz, 2H), 2.98-2.85 (m, 1H),2.67-2.55 (m, 1H), 2.43-2.30 (m, 1H), 2.04-1.93 (m, 1H), 1.11 (t, J=6.9Hz, 3H).

Example 87N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-hydroxyphenyl)acetamide

A. 1-Iodo-2-(methoxymethoxy)benzene

To a stirred solution of 2-iodophenol (3 g, 13.63 mmol) in dichloromethane (30 mL) was added diisopropyl ethyl amine (7.2 mL, 40.89 mmol)followed by chloro methyl methyl ether (1.63 g, 20.45 mmol) at 0° C. andstirred at room temperature for 16 h. The reaction mixture was quenchedwith ice water (30 mL) and extracted with dichloro methane (3×30 mL).The combined organic layers were washed with water (30 mL), brine (30mL), dried over sodium sulfate, filtered and concentrated. The resultantcrude product was purified by silica gel column chromatography (20%ethyl acetate in pet ether) to afford 1-iodo-2-(methoxymethoxy)benzene(2.5 g, 9.61 mmol, 72% yield) as a brown liquid. ¹H NMR (400 MHz, CDCl₃)δ 7.78 (dd, J=8.0, 1.6 Hz, 1H), 7.28 (ddd, J=8.5, 7.4, 1.6 Hz, 1H), 7.07(dd, J=8.4, 1.6 Hz, 1H), 6.76 (ddd, J=8.8, 7.2, 0.8 Hz, 1H), 5.24 (s,2H), 3.52 (s, 3H).

B. Ethyl 2,2-difluoro-2-(2-(methoxymethoxy)phenyl)acetate

To a stirred solution of 1-iodo-2-(methoxymethoxy)benzene (3 g, 8.24mmol) in dimethylsulfoxide (11.5 mL) was added ethyl2-bromo-2,2-difluoroacetate (2.67 g, 13.18 mmol) followed by copperpowder (1.31 g, 20.6 mmol) at 0° C. and stirred at 60° C. for 5 h. Thereaction mixture was quenched with ice water (30 mL) and filteredthrough a Celite pad. The filtrate was extracted with ethyl acetate(3×30 mL) and the combined organic layers were washed with water (30mL), brine (30 mL), dried over sodium sulfate, filtered andconcentrated. The obtained crude product was purified by flashchromatography (20% ethyl acetate in pet ether to afford ethyl2,2-difluoro-2-(2-(methoxymethoxy)phenyl)acetate (1.3 g, 5.0 mmol, 62%yield) as a colorless liquid. MS (ESI) m/z 260.2 [M]⁺.

C. 2,2-Difluoro-2-(2-(methoxymethoxy)phenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(2-(methoxymethoxy)phenyl)acetate (2 g, 7.69 mmol) inmixture of methanol:tetrahydrofuran:water (20 mL, 1:1:1) at 0° C. wasadded lithium hydroxide monohydrate (970 mg, 23.07 mmol) and stirred atroom temperature for 4 h. The volatiles were removed under reducedpressure and the obtained crude was diluted with water (20 mL) andwashed with ethyl acetate (2×15 mL). Aqueous layer was acidified withaqueous potassium bisulfate solution and extracted with ethyl acetate(3×20 mL). The combined organic layers were washed with brine (20 mL),dried over sodium sulfate, filtered and concentrated to afford2,2-difluoro-2-(2-(methoxymethoxy)phenyl)acetic acid (1.2 g, 4.87 mmol,63% yield) as a brown semi solid. MS (ESI) m/z 246.3 [M]⁺.

D.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-hydroxyphenyl)acetamide

To an ice cold solution of2,2-difluoro-2-(2-(methoxymethoxy)phenyl)acetic acid (258 mg, 1.16 mmol)in pyridine (9 mL) was added phosphorus oxychloride (0.27 mL, 2.9 mmol)drop wise and stirred at 0-5° C. for 1 h. Then,3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) was added into the reaction mixtureand stirred at room temperature for 1 h. The reaction mixture wasbasified with aqueous saturated sodium bicarbonate solution andextracted with ethyl acetate (3×15 mL). The combined organic layers werewashed with brine (15 mL), dried over sodium sulfate, filtered andconcentrated. The resultant residue was purified by Reveleris C-18reversed phase column chromatography (50-55% acetonitrile in 0.1%aqueous formic acid) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-hydroxyphenyl)acetamide (33 mg, 0.07 mmol, 8% yield) as white solid. MS (ESI) m/z444.35 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 11.00 (s, 1H), 10.24 (bs,1H), 9.38 (bs, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.51 (s, 1H), 7.47-7.44 (m,2H), 7.34 (dd, J=7.8, 7.5 Hz, 1H), 6.91-6.87 (m, 2H), 5.11 (dd, J=13.5,5.1 Hz, 1H), 4.48 (d, J=4.5 Hz, 2H), 4.46 (d, J=18.0 Hz, 1H), 4.32 (d,J=17.4 Hz, 1H), 2.96-2.86 (m, 1H), 2.58-2.49 (m, 1H), 2.42-2.27 (m, 1H),2.07-1.98 (m, 1H).

Example 88N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(methylamino)phenyl)acetamide

A. Benzyl 2-iodophenylcarbamate

To a stirred solution of 2-iodoaniline (3 g, 13.69 mmol) in 4N sodiumaqueous hydroxide (3 mL), water (10 mL) was added benzyl chloroformate(2.79 g, 16.43 mmol) at 0° C. and stirred at room temperature for 3 h.The reaction mixture was diluted with water (30 mL) and extracted withethyl acetate (3×30 mL). The combined organic layers were washed withwater (30 mL), brine (30 mL), dried over sodium sulfate and concentratedto afford benzyl 2-iodophenylcarbamate (3 g, 8.49 mmol, 62% yield) as acolorless liquid.

¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J=8.8 Hz, 1H), 7.76 (dd, J=11.8 Hz,1.8 Hz, 1H), 7.48-7.32 (m, 6H), 7.02 (brs, 1H), 6.79 (ddd, J=8.0, 7.7,1.8 Hz, 1H), 5.23 (s, 2H).

B. Benzyl 2-iodophenyl(methyl)carbamate

To a stirred solution of benzyl 2-iodophenylcarbamate (1.5 g, 4.24 mmol)in N,N-dimethylformamide (15 mL) was added cesium carbonate (4.13 g,12.72 mmol) followed by iodo methane (0.9 g, 6.37 mmol) at 0° C. andstirred at 60° C. for 5 h. The reaction mixture was diluted with water(25 mL) and extracted with ethyl acetate (3×25 mL). The combined organiclayers were washed with water (25 mL), brine (25 mL), dried over sodiumsulfate, filtered and concentrated. The obtained crude was purified bysilica gel column chromatography using 30% ethyl acetate in pet ether toafford benzyl 2-iodophenyl(methyl)carbamate (1.2 g, 3.26 mmol, 80%yield) as a colorless liquid. MS (ESI) m/z 368.01 [M+1]⁺

C. Ethyl2-(2-((benzyloxycarbonyl)(methyl)amino)phenyl)-2,2-difluoroacetate

To a stirred solution of benzyl 2-iodophenyl(methyl)carbamate (1 g, 2.72mmol) in dimethylsulfoxide (20 mL) was added ethyl2-bromo-2,2-difluoroacetate (0.83 g, 4.08 mmol) followed by copper (0.45g, 7.08 mmol) at 0° C. and stirred at 60° C. for 5 h. The reactionmixture was quenched with ice water and filtered through a Celite pad.The filtrate was extracted with ethyl acetate (3×15 mL) and the combinedorganic layers were washed with water (15 mL), brine (15 mL), dried oversodium sulfate, filtered and concentrated. The obtained crude waspurified by flash chromatography (20% ethyl acetate in pet ether toafford ethyl 2-(2-((benzyloxycarbonyl)(methyl)amino)phenyl)-2,2-difluoroacetate (0.72 g, 1.98 mmol, 73% yield)as a colorless liquid. MS (ESI) m/z 363.1 [M]⁺.

D. 2-(2-((Benzyloxycarbonyl)(methyl)amino)phenyl)-2,2-difluoroaceticacid

To a cold (0° C.) stirred solution of ethyl 2-(2-((benzyloxycarbonyl)(methyl) amino)phenyl)-2,2-difluoroacetate (700 mg, 1.9 mmol) in mixtureof methanol:tetrahydrofuran:water mixture (15 mL, 1:1:1) was addedlithium hydroxide monohydrate (242 mg, 5.78 mmol) and stirred at roomtemperature for 4 h. The volatiles were removed under reduced pressureand the obtained residue was dissolved in water (10 mL), washed withethyl acetate (2×10 mL). Aqueous layer was acidified with aqueouspotassium bisulfate solution and extracted with ethyl acetate (3×15 mL).The combined organic layers were washed with brine (15 mL), dried oversodium sulfate, filtered and concentrated to afford2-(2-((benzyloxycarbonyl)(methyl)amino)phenyl)-2,2-difluoroacetic acid(620 mg, 1.85 mmol, 97% yield) as a semi solid. MS (ESI) m/z 336.4[M+1]⁺.

E. Benzyl2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methylamino)-1,1-difluoro-2-oxoethyl)phenyl(methyl)carbamate

To an ice cold solution of2-(2-((benzyloxycarbonyl)(methyl)amino)phenyl)-2,2-difluoroacetic acid(325 mg, 0.97 mmol) in pyridine (9 mL) was added phosphorus oxychloride(0.27 mL, 2.9 mmol) in drop wise and stirred at 0-5° C. for 1 h. Then,3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) was added into the reaction mixtureand stirred at room temperature for 2 h. The reaction mixture wasbasified with aqueous saturated sodium bicarbonate solution andextracted with ethyl acetate (3×15 mL). The combined organic layers werewashed with brine (15 mL), dried over sodium sulfate, filtered andconcentrated. The resultant residue was purified by Reveleris C-18reversed phase column chromatography (50-55% acetonitrile in 0.1%aqueous formic acid) to afford benzyl2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methylamino)-1,1-difluoro-2-oxoethyl)phenyl(methyl)carbamate(150 mg, 0.25 mmol, 26% yield) as white solid. MS (ESI) m/z 591.62[M+1]⁺.

F.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(methylamino)phenyl)acetamide

To a stirred solution of benzyl2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methylamino)-1,1-difluoro-2-oxoethyl)phenyl(methyl)carbamate(0.1 g, 0.169 mmol) in methanol (15 mL) was added a slurry of 10%palladium hydroxide (10 mg) in methanol under nitrogen stream andstirred under 60 psi hydrogen pressure at room temperature for 6 h. Thehydrogen atmosphere was evacuated and reaction mixture was filteredthrough a Celite pad and the filtrate was concentrated. The resultantresidue was purified by Reveleris C-18 reversed phase columnchromatography (50-55% acetonitrile in 0.1% aqueous formic acid) toafford to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(methylamino)phenyl)acetamide (62 mg, 0.13 mmol, 80% yield) as a white solid.MS (ESI) m/z 457.23 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H),9.56 (t, J=6.0 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.42 (s, 1H), 7.39-7.28(m, 3H), 6.70-6.65 (m, 2H), 5.43 (q, J=4.2 Hz, 1H), 5.10 (dd, J=13.5,5.1 Hz, 1H), 4.47 (d, J=6.0 Hz, 2H), 4.42 (d, J=17.9 Hz, 1H), 4.28 (d,J=17.1 Hz, 1H), 2.91-2.85 (m, 1H), 2.74 (d, J=4.8 Hz, 3H), 2.62-2.50 (m,1H), 2.43-2.34 (m, 1H), 2.01-1.99 (m, 1H).

Example 89N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxy-2-(trifluoromethyl)phenyl)acetamide

A. 1-Bromo-4-isopropoxy-2-(trifluoromethyl)benzene

To a stirred solution of 4-bromo-3-(trifluoromethyl)phenol (5 g, 20.83mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate(8.6 g, 62.49 mmol) followed by isopropyl iodide (3.1 mL, 31.24 mmol)and stirred at 80° C. for 4 h. The reaction mixture was filtered andwater (50 mL) was added and extracted with ethyl acetate (2×60 mL). Thecombined organic layers were washed with brine (50 mL), dried oversodium sulphate and concentrated. The resultant residue was purified bycolumn chromatography (100-200 silica) using 0-10% ethyl acetate inhexanes to afford 1-bromo-4-isopropoxy-2-(trifluoromethyl)benzene (3.5g, 12.41 mmol, 59% yield). LCMS (ESI) m/z 284.38 [M+2]⁺.

B. 1-Iodo-4-isopropoxy-2-(trifluoromethyl)benzene

To a stirred solution of 1-bromo-4-isopropoxy-2-(trifluoromethyl)benzene(3.5 g, 12.41 mmol) in 1,4-dioxane (30 mL) was added sodium iodide (5.58g, 37.23 mmol), copper iodide (471 mg, 2.48 mmol),trans-N,N′-dimethylcyclohexane-1,2-diamine (529 mg, 3.72 mmol) at roomtemperature and stirred at 110° C. for 16 h in sealed tube. The reactionmixture was quenched with water (20 mL) and extracted with ethyl acetate(3×300 mL). The combined organic layers were washed with water (2×50mL), brine (50 mL), dried over sodium sulphate and concentrated toafford 1-iodo-4-isopropoxy-2-(trifluoromethyl)benzene (3 g, 9.09 mmol,73% yield) as brown liquid. MS (ESI) m/z 331.0 [M]⁺.

C. Ethyl 2,2-difluoro-2-(2-methyl-4-(trifluoromethoxy)phenyl)acetate

To a stirred solution of 1-iodo-4-isopropoxy-2-(trifluoromethyl)benzene(3 g, 9.09 mmol) in dimethyl sulfoxide (25 mL) was added copper (1.5 g,23.63 mmol) and ethyl 2-iodo-2,2-difluoroacetate (2.005 mL, 13.63 mmol)at room temperature and stirred at 55° C. for 2 h. The reaction mixturewas neutralized with aqueous saturated ammonium chloride (50 mL)solution and extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with water (2×100 mL), brine (100 mL), driedover sodium sulphate and concentrated to afford ethyl2,2-difluoro-2-(4-isopropoxy-2-(trifluoromethyl)phenyl)acetate (2.5 g,7.66 mmol, 84%). GCMS (ESI) m/z 326.2.

D. 2,2-Difluoro-2-(4-isopropoxy-2-(trifluoromethyl)phenyl)acetic acid

To a cold (0° C.) stirred solution of ethyl ethyl2,2-difluoro-2-(4-isopropoxy-2-(trifluoromethyl)phenyl)acetate (2.5 g,7.66 mmol) in tetrahydrofuran:Methanol:water (30 mL, 1:1:1) was addedlithium hydroxide (1.6 g, 38.34 mmol) and stirred at room temperaturefor 6 h. The reaction mixture was concentrated and the residue wasneutralized with 10% aqueous hydrochloric acid (10 mL) and extractedwith ethyl acetate (2×20 mL). The combined organic layer was washed withbrine (20 mL), dried over sodium sulphate and concentrated to afford2,2-difluoro-2-(4-isopropoxy-2-(trifluoromethyl)phenyl)acetic acid (1.8g, 6.04 mmol, 78% yield) as a brown liquid. The crude was taken to thenext step without further purification.

E.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxy-2-(trifluoromethyl)phenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(4-isopropoxy-2-(trifluoromethyl)phenyl)acetic acid (380mg, 1.165 mmol) in pyridine was added POCl₃ (0.27 mL, 2.91 mmol)dropwise and stirred at 0-5° C. for 1 h and then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.968 mmol) and continued stirring at roomtemperature for 30 min. The reaction mixture was neutralized withaqueous saturated sodium bicarbonate (up to pH-8) and extracted withethyl acetate (3×50 mL). The combined organic layers were washed withwater (2×10 mL), brine (10 mL), dried over sodium sulphate andconcentrated. The resultant residue was purified by Reveleris C-18reversed phase column chromatography using 40-60% acetonitrile inaqueous formic acid (0.1%) to giveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxy-2-(trifluoromethyl)phenyl)acetamide(48 mg, 0.086 mmol, 10% yield) as an off white solid. MS (ESI) m/z554.03 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.58 (t, J=5.6Hz, 1H), 7.73-7.64 (m, 2H), 7.47 (s, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.36(d, J=8.8 Hz, 1H), 7.32-7.28 (m, 1H), 5.11 (dd, J=13.2, 5.1 Hz, 1H),5.00-4.25 (m, 4H), 3.00-2.85 (m, 1H), 2.69-2.55 (m, 1H), 2.44-2.35 (m,J=2.0 Hz, 1H), 2.05-1.95 (m, 1H), 1.35-1.25 (m, 6H).

Example 90N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methylcyclohexyl)acetamide

A. Ethyl 2,2-difluoro-2-(1-hydroxy-4-methylcyclohexyl)acetate

To a stirred solution of 4-methylcyclohexanone (1 g, 8.92 mmol) intetrahydrofuran (20 mL) was added catalytic amount of anhydrouscerium(III) chloride (0.22 g, 0.89 mmol), followed by activated zincdust (0.75 g, 11.6 mmol) and ethyl 2-bromo-2,2-difluoroacetate (1.13 mL,11.6 mmol) at 0° C. and stirred at room temperature for 16 h. Thereaction mixture was diluted with water (20 mL) and extracted with ethylacetate (3×15 mL). The combined organic layers were washed with water(15 mL), brine (15 mL), dried over sodium sulfate, filtered andconcentrated. The obtained crude was purified by silica gel columnchromatography (30% ethyl acetate in pet ether) to afford ethyl2,2-difluoro-2-(1-hydroxy-4-methylcyclohexyl)acetate (0.9 g, 3.81 mmol,41% yield) as a colorless liquid. ¹H NMR (400 MHz, DMSO-d₆) δ 5.33 (d,J=13.2 Hz, 1H), 4.27 (q, J=7.2 Hz, 2H), 2.37 (dt, J=13.3, 7.8 Hz, 1H),2.18-2.13 (m, 1H), 1.94-1.86 (m, 1H), 1.78-1.70 (m, 4H), 1.48-1.39 (m,2H), 1.26 (t, J=7.3 Hz, 3H), 0.91 (dt, J=18.8, 5.6 Hz, 3H).

B. Ethyl 2,2-difluoro-2-(4-methylcyclohex-1-enyl)acetate

To a stirred solution of ethyl2,2-difluoro-2-(1-hydroxy-4-methylcyclohexyl)acetate (1.8 g, 7.62 mmol)in pyridine (18 mL), was added thionyl chloride (9 mL, 76.27 mmol) at 0°C. and stirred at room temperature for 16 h. The reaction mixture wasdiluted with water (20 mL) and basified with aqueous sodium bicarbonatesolution and extracted with ethyl acetate (3×20 mL). The combinedorganic layers were washed with water (20 mL), brine (20 mL), dried oversodium sulfate, filtered and concentrated. The obtained crude productwas purified by silica gel column chromatography using 20% ethyl acetatein pet ether to afford ethyl2,2-difluoro-2-(4-methylcyclohex-1-enyl)acetate (1 g, 4.23 mmol, 62%yield) as a colorless liquid. MS (ESI) m/z 218.2 [M]⁺.

C. Ethyl 2,2-difluoro-2-(4-methylcyclohexyl)acetate

To a stirred solution of ethyl2,2-difluoro-2-(4-methylcyclohex-1-enyl)acetate (700 mg, 3.21 mmol) inethyl acetate (15 mL) was added a slurry of 10% palladium hydroxide (200mg) in ethyl acetate under nitrogen stream and stirred under hydrogenballoon pressure at room temperature for 4 h. The hydrogen atmospherewas evacuated and reaction mixture was filtered through a Celite pad,filtrate was concentrated to afford ethyl2,2-difluoro-2-(4-methylcyclohexyl)acetate (500 mg, 1.3 mmol, 37% yield)as a colorless liquid. MS (ESI) m/z 220.2 [M]⁺.

D. 2,2-Difluoro-2-(4-methylcyclohexyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(4-methylcyclohexyl)acetate (500 mg, 2.27 mmol) inmixture of tetrahydrofuran:methanol:water (15 mL, 1:1:1) was addedlithium hydroxide monohydrate (286 mg, 6.81 mmol) and stirred at roomtemperature for 4 h. The volatiles were removed under reduced pressureand the obtained residue was dissolved in water (10 mL) and washed withethyl acetate (2×10 mL). Aqueous layer was acidified with 1Nhydrochloride and extracted with ethyl acetate (3×10 mL). The combinedorganic layers were washed with brine (10 mL), dried over sodiumsulfate, filtered and solvent was concentrated to afford2,2-difluoro-2-(4-methylcyclohexyl)acetic acid (280 mg, 1.45 mmol, 64%yield) as semi-solid compound. ¹H NMR (300 MHz, CDCl₃) δ 8.26 (brs, 1H),2.04-2.02 (m, 1H), 1.85-1.78 (m, 3H), 1.60-1.52 (m, 2H), 1.36-1.24 (m,2H), 1.01-0.87 (m, 2H), 0.90 (d, J=6.3 Hz, 3H).

E.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methylcyclohexyl)acetamide

To an ice cold solution of 2,2-difluoro-2-(4-methylcyclohexyl)aceticacid (186 mg, 0.97 mmol) in pyridine (9 mL) was added phosphorusoxychloride (0.27 mL, 2.9 mmol) drop wise and stirred at 0-5° C. for 1h. Then, 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) was added into the reaction mixtureand stirred at room temperature for 2 h. The reaction mixture wasbasified with aqueous saturated sodium bicarbonate solution andextracted with ethyl acetate (3×15 mL). The combined organic layers werewashed with brine (15 mL), dried over sodium sulfate, filtered andconcentrated. The resultant residue was purified by Reveleris C-18reversed phase column chromatography (50-55% acetonitrile in 0.1%aqueous formic acid) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methylcyclohexyl)acetamide (45 mg, 0.1 mmol, 10% yield) as white solid. MS (ESI) m/z448.19 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.35 (t, J=6.0Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J=8.1 Hz, 1H),5.11 (dd, J=13.2, 5.4 Hz, 1H), 4.45 (d, J=16.5 Hz, 1H), 4.44 (d, J=6.6Hz, 2H), 4.31 (d, J=17.4 Hz, 1H), 2.92-2.87 (m, 1H), 2.63-2.57 (m, 1H),2.41-2.36 (m, 1H), 2.02-1.98 (m, 2H), 1.68-1.65 (m, 3H), 1.48-1.42 (m,3H), 1.24-1.15 (m, 2H), 0.99-0.86 (m, 1H), 0.87 (dd, J=6.9, 6.3 Hz, 3H).

Example 91N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-isopropoxyethoxy)phenyl)acetamide

A. Ethyl 2,2-difluoro-2-(3-(2-isopropoxyethoxy)phenyl)acetate

To a stirred solution of ethyl 2,2-difluoro-2-(3-hydroxyphenyl)acetate(200 mg, 0.92 mmol) in tetrahydrofuran (10 mL) was added diisopropylazodicarboxylate (373 mg, 1.85 mmol) followed by triphenylphosphine (485mg, 1.85 mmol) and 2-isopropoxyethanol (96.2 mg, 0.92 mmol) at 0° C. andstirred at room temperature for 16 h. The reaction mixture was quenchedwith ice water and extracted with ethyl acetate (3×10 mL). The combinedorganic layers were washed with water (10 mL), brine (10 mL), dried oversodium sulfate, filtered and concentrated. The obtained crude waspurified by flash chromatography (20% ethyl acetate in pet ether) toafford ethyl 2,2-difluoro-2-(3-(2-isopropoxyethoxy)phenyl)acetate (100mg, 0.33 mmol, 36% yield) as a colorless liquid. GCMS (ESI) m/z 302.6[M]⁺.

B. 2,2-Difluoro-2-(3-(2-isopropoxyethoxy)phenyl)acetic acid

To an ice cold stirred solution of ethyl 2,2-difluoro-2-(3-(2-isopropoxyethoxy) phenyl)acetate (210 mg, 0.69 mmol) in mixture ofmethanol:tetrahydrofuran:water (10 mL, 1:1:1) was added lithiumhydroxide monohydrate (87 mg, 2.086 mmol) and stirred at roomtemperature for 4 h. The volatiles were removed under reduced pressureand the obtained residue was dissolved in water (10 mL), washed withethyl acetate (2×6 mL). Aqueous layer was acidified with aqueouspotassium bisulfate solution and extracted with ethyl acetate (3×10 mL).The combined organic layers were washed with brine (10 mL), dried oversodium sulfate, filtered and concentrated to afford2,2-difluoro-2-(3-(2-isopropoxyethoxy)phenyl)acetic acid (180 mg, 0.65mmol, 95% yield) as a semi solid. ¹H NMR (300 MHz, CDCl₃) δ 7.29 (dd,J=8.2, 7.5 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.11 (s, 1H), 6.99 (d, J=7.5Hz, 1H), 4.11 (t, J=5.4 Hz, 2H), 3.82 (t, J=5.1 Hz, 2H), 3.75 (sep,J=6.0 Hz, 1H), 1.23 (d, J=5.7 Hz, 6H).

C.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-isopropoxyethoxy)phenyl)acetamide

To an ice cold solution of2,2-difluoro-2-(3-(2-isopropoxyethoxy)phenyl)acetic acid (221 mg, 0.81mmol) in pyridine (9 mL) was added phosphorus oxychloride (371 mg, 2.47mmol) in drop wise and stirred at 0-5° C. for 1 h. Then,3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (250 mg, 0.81 mmol) was added into the reaction mixtureand stirred at room temperature for 1 h. The reaction mixture wasbasified with aqueous saturated sodium bicarbonate solution andextracted with ethyl acetate (3×15 mL). The combined organic layers werewashed with brine (15 mL), dried over sodium sulfate, filtered andconcentrated. The resultant residue was purified by Reveleris C-18reversed phase column chromatography (50-55% acetonitrile in 0.1%aqueous formic acid) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-isopropoxyethoxy)phenyl)acetamide (62 mg, 0.116 mmol, 15% yield) as white solid.MS (ESI) m/z 529.9 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H),9.60 (t, J=6.0 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H),7.40 (s, 1H), 7.36 (d, J=7.5 Hz, 1H), 7.15-7.12 (m, 3H), 5.10 (dd,J=13.5, 5.1 Hz, 1H), 4.45 (d, J=5.7 Hz, 2H), 4.42 (d, J=18.0 Hz, 1H),4.27 (d, J=17.4 Hz, 1H), 4.08 (t, J=4.5 Hz, 2H), 3.69 (t, J=4.8 Hz, 2H),3.62 (sep, J=5.7 Hz, 1H), 2.98-2.87 (m, 1H), 2.66-2.56 (m, 1H),2.45-2.30 (m, 1H), 2.04-1.94 (m, 1H), 1.09 (d, J=6.3 Hz, 6H).

Example 92N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-hydroxyphenyl)acetamide

A. 1-Iodo-3-(methoxymethoxy)benzene

To a stirred solution of 3-iodophenol (1 g, 4.54 mmol) indichloromethane (10 mL) was added N,N-diisopropyl ethyl amine (2.4 mL,13.63 mmol) followed by chloro methyl methyl ether (0.5 mL, 6.81 mmol)at 0° C. and stirred at room temperature for 2 h. The reaction mixturewas quenched with ice water and extracted with dichloromethane (2×100mL). The combined organic layers were washed with water (50 mL), brine(50 mL), dried over sodium sulfate, filtered and concentrated to afford1-iodo-3-(methoxymethoxy)benzene (1.0 g, 3.78 mmol, 83% yield). GC MS(m/z) 264.0 [M]⁺.

B. Ethyl 2,2-difluoro-2-(3-(methoxymethoxy)phenyl)acetate

To a stirred solution of 1-iodo-3-(methoxymethoxy)benzene (800 mg, 3.03mmol) in dimethylsulfoxide (10 mL) was added ethyl2-bromo-2,2-difluoroacetate (738 mg, 3.97 mmol) followed by copper (501mg, 7.88 mmol) and stirred at 55° C. for 5 h. The reaction mixture wasquenched with aqueous ammonium chloride solution and was extracted withethyl acetate (3×50 mL). The combined organic layers were washed withwater (50 mL), brine (50 mL), dried over sodium sulfate, filtered andconcentrated to afford ethyl2,2-difluoro-2-(3-(methoxymethoxy)phenyl)acetate (700 mg, 2.69 mmol, 89%yield). GC MS (m/z) 260.2 [M]⁺.

C. 2,2-Difluoro-2-(3-(methoxymethoxy)phenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(3-(methoxymethoxy)phenyl)acetate (700 mg, 2.69 mmol) inmethanol-tetrahydrofuran-water mixture (15 mL, 1:1:1) was added lithiumhydroxide monohydrate (339 mg, 8.07 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was diluted with water (50 mL)and acidified with aqueous potassium bisulfate solution and extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith brine (50 mL), dried over sodium sulfate, filtered and concentratedto afford 2,2-difluoro-2-(3-(methoxymethoxy)phenyl)acetic acid (400 mg,1.72 mmol, 64% yield). LCMS (ESI) m/z 231.31 [M−1]⁻.

D.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(methoxymethoxy)phenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(3-(methoxymethoxy)phenyl)acetic acid (300 mg, 1.29 mmol)in pyridine (5 mL) was added phosphoryl chloride (0.4 mL, 3.87 mmol)dropwise and stirred at 0-5° C. for 1 h, and then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (400 mg, 1.29 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×30 mL), brine (30 mL),dried over sodium sulphate and concentrated to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(methoxymethoxy)phenyl)acetamide(250 mg, 0.51 mmol, 40% yield). LCMS (ESI) m/z 488.39 [M+1]⁺.

E.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-hydroxyphenyl)acetamide

To a cold (0° C.) stirred solution ofN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(methoxymethoxy)phenyl)acetamide(250 mg, 0.51 mmol) in 1,4-dioxane (5 mL) was added 1,4-dioxane.HCl (2.0mL) dropwise and stirred at room temperature for 1 h. The reactionmixture was neutralized with aqueous saturated sodium bicarbonate (up topH-8) and extracted with ethyl acetate (3×50 mL). The combined organiclayer was washed with water (2×30 mL), brine (30 mL) and dried oversodium sulphate and was concentrated. The resultant residue was purifiedby Reveleris C-18 reversed phase column chromatography using 45-50%acetonitrile in aqueous formic acid (0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-hydroxyphenyl)acetamide(75 mg, 0.16 mmol, 33.0% yield) as an off-white solid. LCMS (ESI) m/z444.13 [M+1]⁺. ¹H NMR (300 MHz, dmso) δ=10.98 (s, 1H), 9.87 (s, 1H),9.62-9.53 (m, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.42-7.27 (m, 4H), 7.02-6.68(m, 3H), 5.10 (br dd, J=5.0, 13.4 Hz, 1H), 4.50-4.22 (m, 4H), 2.96-2.82(m, 1H), 2.68-2.54 (m, 1H), 2.44-2.30 (m, 1H), 2.05-1.93 (m, 1H).

Example 93N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)acetamide

A. Ethyl 2,2-difluoro-2-(3-formylphenyl)acetate

To a stirred solution of 4-iodobenzaldehyde (5 g, 21.55 mmol) indimethylsulfoxide (50 mL) was added ethyl 2-bromo-2,2-difluoroacetate(6.0 mL, 43.11 mmol), copper (4.0 g, 56.03 mmol) and stirred for 4 h at55° C. The reaction mixture was neutralized with aqueous saturatedammonium chloride solution and extracted with ethyl acetate (3×100 mL).The combined organic layers were washed with water (2×50 mL), brine (50mL), dried over sodium sulphate and concentrated to afford ethyl2,2-difluoro-2-(3-formylphenyl)acetate (3.5 g, 15.35 mmol, 71%). GC MS(m/z) 228.2.

B. Ethyl2,2-difluoro-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)acetate

To a stirred solution of ethyl 2,2-difluoro-2-(3-formylphenyl)acetate(1.0 g, 4.38 mmol) in ethanol (25 mL) was added 1-methylpiperazine (878mg, 8.77 mmol), acetic acid (526 mg, 8.77 mmol) and stirred at 0° C. for1 h. To this reaction mixture was then added sodium cyanoborohydride(551 mg, 8.77 mmol) and stirred at room temperature for 3 h. Thereaction mixture was quenched with water (100 mL) and extracted withethyl acetate (3×100 mL). The combined organic layers were washed withwater (2×100 mL), brine (100 mL), dried over sodium sulphate andconcentrated to afford ethyl2,2-difluoro-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)acetate (1.0 g,3.20 mmol, 74% yield). LCMS (ESI) m/z 313.53[M+1]⁺

C. 2,2-Difluoro-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)acetate (1.0 g,3.20 mmol) in tetrahydrofuran:methanol:water mixture (1:1:1, 30 mL) wasadded lithium hydroxide monohydrate (403 mg, 5.01 mmol) and stirred atroom temperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous potassium bisulphate (10 mL)and extracted with ethyl acetate (2×50 mL). The combined organic layerswere washed with brine (20 mL), dried over sodium sulphate andconcentrated to give2,2-difluoro-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)acetic acid(750 mg, 2.64 mmol, 82% yield). LCMS (ESI) m/z 284.9[M+1]⁺.

D.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)acetic acid(350 mg, 1.23 mmol) in pyridine (5 mL) was added phosphoryl chloride(0.3 mL, 3.69 mmol) and stirred at 0-5° C. for 1 h. Then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (381 mg, 1.23 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (2×25 mL). Thecombined organic layers were washed with water (15 mL), brine (15 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase column chromatography using45-50% acetonitrile in aqueous formic acid (0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)acetamide(40 mg, 0.26 mmol, 6% yield) as a pale yellow solid. LCMS (ESI) m/z540.40 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ10.99 (s, 1H), 9.67 (t, J=5.8Hz, 1H), 7.87 (br s, 2H), 7.67-7.55 (m, 3H), 7.45-7.33 (m, 2H), 5.10(dd, J=4.9, 13.3 Hz, 1H), 4.48-4.24 (m, 6H), 3.65-3.03 (m, 8H),3.01-2.82 (m, 4H), 2.66-2.54 (m, 1H), 2.48-2.30 (m, 1H), 2.29-1.82 (m,1H).

Example 94N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methyl-2-(trifluoromethyl)phenyl)acetamide

A. 1-Iodo-4-methyl-2-(trifluoromethyl)benzene

To a stirred solution of 1-bromo-4-methyl-2-(trifluoromethyl)benzene(1.0 g, 4.18 mmol) in 1,4-dioxane (10 mL) was added sodium iodide (1.3g, 8.36 mmol), copper iodide (40 mg, 0.20 mmol),trans-N,N′-dimethylcyclohexane-1,2-diamine (66 mg, 0.46 mmol) at roomtemperature and stirred at 110° C. for 16 h in sealed tube. The reactionmixture was quenched with water (100 mL) and extracted with ethylacetate (3×100 mL). The combined organic layers were washed with water(2×50 mL), brine (50 mL), dried over sodium sulphate and concentrated togive 1-Iodo-4-methyl-2-(trifluoromethyl)benzene (900 mg, 3.14 mmol, 75%yield). GCMS (m/z) 286.

B. Ethyl 2,2-difluoro-2-(4-methyl-2-(trifluoromethyl)phenyl)acetate

To a stirred solution of 1-iodo-4-methyl-2-(trifluoromethyl)benzene (900mg, 3.14 mmol) in dimethylsulfoxide (10 mL) was added ethyl2-bromo-2,2-difluoroacetate (1.3 g, 6.29 mmol), copper (520 mg, 8.18mmol) and stirred at 55° C. for 16 h. The reaction mixture wasneutralized with aqueous saturated ammonium chloride solution andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×50 mL), brine (50 mL), dried over sodium sulphateand concentrated to afford ethyl2,2-difluoro-2-(4-methyl-2-(trifluoromethyl)phenyl)acetate (800 mg, 2.83mmol, 90%). GCMS (m/z) 282.1.

C. 2,2-Difluoro-2-(4-methyl-2-(trifluoromethyl)phenyl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(4-methyl-2-(trifluoromethyl)phenyl)acetate (800 mg, 2.83mmol) in tetrahydrofuran—Methanol-water (15 mL, 1:1:1) was added lithiumhydroxide monohydrate (357 mg, 8.51 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous potassium bisulphate (10 mL)and extracted with ethyl acetate (2×50 mL). The combined organic layerswere washed with brine (30 mL), dried over sodium sulphate andconcentrated to afford2,2-difluoro-2-(4-methyl-2-(trifluoromethyl)phenyl)acetic acid (400 mg,1.57 mmol, 56% yield). LCMS (ESI) m/z 253.32 [M−1]⁻.

D.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methyl-2-(trifluoromethyl)phenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(4-methyl-2-(trifluoromethyl)phenyl)acetic acid (400 mg,1.57 mmol) in pyridine (5 mL) was added phosphoryl chloride (0.4 mL,4.72 mmol) drop wise and stirred at 0-5° C. for 1 h. To this reactionmixture was added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (487 mg, 1.57 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×30 mL), brine (30 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase column chromatography using45-50% acetonitrile in aqueous formic acid (0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methyl-2-(trifluoromethyl)phenyl)acetamide(50 mg, 0.09 mmol, 6.0% yield) as an off-white solid. LCMS (ESI) m/z510.28 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ=10.98 (s, 1H), 9.62 (br t,J=6.1 Hz, 1H), 7.78-7.60 (m, 4H), 7.75 (s, 1H), 7.41 (d, J=7.6 Hz, 1H),5.11 (dd, J=5.1, 13.5 Hz, 1H), 4.51-4.21 (m, 4H), 2.98-2.85 (m, 1H),2.65-2.54 (m, 1H), 2.47-2.31 (m, 4H), 2.04-1.96 (m, 1H).

Example 95N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)acetamide

A. 1-Iodo-3-(methoxymethoxy)benzene

To a stirred solution of 3-iodophenol (1 g, 4.54 mmol) indichloromethane (10 mL) was added N,N-diisopropyethylamine (2.4 mL,13.63 mmol) followed by chloro methyl methyl ether (0.5 mL, 6.81 mmol)at 0° C. and stirred at room temperature for 2 h. The reaction mixturewas quenched with ice water and extracted with dichloromethane (3×15mL). The combined organic layers were washed with water (15 mL), brine(15 mL), dried over sodium sulfate, filtered and concentrated to afford1-iodo-3-(methoxymethoxy)benzene (1.0 g, 3.78 mmol, 83% yield). MS (ESI)m/z 264.0 [M]⁺.

B. Ethyl 2,2-difluoro-2-(3-(methoxymethoxy)phenyl)acetate

To a stirred solution of 1-iodo-3-(methoxymethoxy)benzene (800 mg, 3.03mmol) in dimethyl sulfoxide (10 mL) was added ethyl2-bromo-2,2-difluoroacetate (738 mg, 3.97 mmol) followed by copper (501mg, 7.88 mmol) and stirred at 55° C. for 5 h. The reaction mixture wasquenched with aqueous ammonium chloride solution and was extracted withethyl acetate (3×15 mL). The combined organic layers were washed withwater (15 mL), brine (15 mL), dried over sodium sulfate, filtered andconcentrated to afford ethyl2,2-difluoro-2-(3-(methoxymethoxy)phenyl)acetate (700 mg, 2.69 mmol, 89%yield). MS (ESI) m/z 260.2 [M]⁺.

C. Ethyl 2,2-difluoro-2-(3-hydroxyphenyl)acetate

To an ice cold solution of ethyl2,2-difluoro-2-(3-(methoxymethoxy)phenyl)acetate (1 g, 3.84 mmol) in1,4-dioxane (5 mL) was added 1,4-dioxane.HCl (5 mL) at 0° C. and stirredat room temperature for 3 h. The volatiles were removed under reducedpressure and obtained crude was purified by flash column chromatography(20% ethyl acetate in pet ether) to afford ethyl2,2-difluoro-2-(3-hydroxyphenyl)acetate (0.7 g, 3.24 mmol, 84% yield) ascolorless liquid. MS (ESI) m/z 216.1 [M]⁺.

D. Ethyl 2,2-difluoro-2-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)acetate

To a stirred solution of ethyl 2,2-difluoro-2-(3-hydroxyphenyl)acetate(1 g, 4.63 mmol) in tetrahydrofuran (10 mL) were sequentially addeddiisopropyl azodicarboxylate (1.87 g, 9.26 mmol), triphenylphosphine(2.42 g, 9.26 mmol) and 2-(2-methoxyethoxy)ethanol (0.55 g, 4.63 mmol)at 0° C. and stirred at room temperature for 16 h. The reaction mixturewas quenched with ice water and extracted with ethyl acetate (3×15 mL).The combined organic layers were washed with water (15 mL), brine (15mL), dried over sodium sulfate, filtered and concentrated. The obtainedcrude was purified by flash column chromatography (20% ethyl acetate inpet ether) to afford ethyl2,2-difluoro-2-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)acetate (0.5 g, 1.57mmol, 34% yield) as a colorless liquid. GCMS (ESI) m/z 318.6 [M]⁺.

E. 2,2-Difluoro-2-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)acetic acid

To an ice cold solution of ethyl 2,2-difluoro-2-(3-(2-(2-methoxyethoxy)ethoxy) phenyl) acetate (500 mg, 1.57 mmol) in mixture ofmethanol:tetrahydrofuran:water (15 mL, 1:1:1) was added lithiumhydroxide monohydrate (198 mg, 4.71 mmol) and stirred at roomtemperature for 4 h. The volatiles were removed under reduced pressureand the obtained crude product was dissolved in water (10 mL), washedwith ethyl acetate (2×8 mL). Then, the aqueous layer was acidified withaqueous potassium bisulfate solution and extracted with ethyl acetate(3×10 mL). The combined organic layers were washed with brine (10 mL),dried over sodium sulfate, filtered and concentrated to afford2,2-difluoro-2-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)acetic acid (300 mg,0.65 mmol, 84% yield) as a semi solid. MS (ESI) m/z 289.36 [M−1]⁺.

F.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)acetamide

To an ice cold solution of2,2-difluoro-2-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)acetic acid (375 mg,1.29 mmol) in pyridine (9 mL) was added phosphorus oxychloride (593 mg,3.88 mmol) in drop wise and stirred at 0-5° C. for 1 h. Then,3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (400 mg, 1.29 mmol) was added into the reaction mixtureand stirred at room temperature for 2 h. The reaction mixture wasbasified with aqueous saturated sodium bicarbonate solution andextracted with ethyl acetate (3×15 mL). The combined organic layers werewashed with brine (15 mL), dried over sodium sulfate, filtered andconcentrated. The resultant residue was purified by Reveleris C-18reversed phase column chromatography (50-55% acetonitrile in 0.1%aqueous formic acid) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)acetamide(46 mg, 0.08 mmol, 7% yield) as white solid. MS (ESI) m/z 546.06 [M+1]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (bs, 1H), 9.60 (t, J=6.3 Hz, 1H), 7.67(d, J=7.5 Hz, 1H), 7.44 (dd, J=8.1, 7.8 Hz, 1H), 7.40 (s, 1H), 7.37 (d,J=7.8 Hz, 1H), 7.16-7.12 (m, 3H), 5.10 (dd, J=13.2, 5.1 Hz, 1H), 4.45(d, J=5.7 Hz, 2H), 4.41 (d, J=18.2 Hz, 1H), 4.27 (d, J=17.7 Hz, 1H),4.11 (t, J=4.2 Hz, 2H), 3.73 (t, J=4.5 Hz, 2H), 3.58 (t, J=4.5 Hz, 2H),3.45 (t, J=5.1 Hz, 2H), 3.24 (s, 3H), 2.98-2.83 (m, 1H), 2.67-2.53 (m,1H), 2.44-2.30 (m, 1H), 2.05-1.94 (m, 1H).

Example 962-(3-(2-(Dimethylamino)ethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamidehydrochloride

A. 2-(3-Iodophenoxy)-N,N-dimethylethanamine

To a stirred solution of 3-iodophenol (2 g, 9.09 mmol) in acetone (20mL) was added 2-chloro-N,N-dimethylethanamine hydrochloride (1.57 g,10.90 mmol), potassium carbonate (5.07 g, 36.36 mmol) and stirred for 16h at 55° C. The reaction mixture was quenched with water (50 mL) andextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with water (2×100 mL), brine (100 mL), dried over sodiumsulphate and concentrated. The resultant residue was purified by columnchromatography (silica-gel 100-200) 100% hexane as a eluent to afford2-(3-Iodophenoxy)-N,N-dimethylethanamine (1.5 g, 5.22 mmol, 57% yield)as brown liquid. MS (ESI) m/z 291[M]⁺.

B. Ethyl 2-(3-(2-(dimethylamino)ethoxy)phenyl)-2,2-difluoroacetate

To a stirred solution of 2-(3-Iodophenoxy)-N,N-dimethylethanamine (1.5g, 5.22 mmol) in dimethyl sulfoxide (20 mL) was added ethyl2-bromo-2,2-difluoroacetate (1.36 mL, 10.45 mmol) followed by copper(0.86 g, 13.58 mmol) and stirred for 16 h at 50° C. The reaction mixturewas neutralized with aqueous saturated ammonium chloride solution andextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with water (2×100 mL), brine (10 mL), dried over sodiumsulphate and concentrated to afford ethyl2-(3-(2-(dimethylamino)ethoxy)phenyl)-2,2-difluoroacetate (1.5 g crude)as a brown liquid. MS (ESI) m/z 288.4[M]⁺.

C. 2-(3-(2-(Dimethylamino)ethoxy)phenyl)-2,2-difluoroacetic acid

To a cold (0° C.) stirred solution of ethyl2-(3-(2-(dimethylamino)ethoxy)phenyl)-2,2-difluoroacetate (1.0 g, 3.48mmol) in in methanol/tetrahydrofuran/water (20 mL, 1:1:1) was addedlithium hydroxide monohydrate (438.4 mg, 10.44 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous potassium bisulphate (10 mL)and extracted with ethyl acetate (2×50 mL). The combined organic layerswere washed with brine (20 mL), dried over sodium sulphate andconcentrated to afford2-(3-(2-(dimethylamino)ethoxy)phenyl)-2,2-difluoroacetic acid (600 mg)as a brown semi solid which was taken to the next step without furtherpurification.

D.2-(3-(2-(Dimethylamino)ethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamidehydrochloride

To a cold (0° C.) stirred solution of2-(3-ethoxypyridin-2-yl)-2,2-difluoroacetic acid (252 mg, 1.16 mmol) inpyridine (20 mL) was added phosphoryl chloride (446.4 mg, 2.91 mmol)dropwise and stirred at 0-5° C. for 30 min. and then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) and stirred at room temperature for 2h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×50 mL), brine (50 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase column chromatography using45-50% acetonitrile in aqueous formic acid (0.1%) to afford2-(3-(2-(dimethylamino)ethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamidehydrochloride (50 mg, 0.07 mmol, 7.5% yield) as an off-white solid. MS(ESI) m/z 515.13 [M+1¹H NMR (400 MHz, DMSO-d₆) ppm 10.99 (s, 1H), 10.31(br s, 1H), 9.68 (br t, J=5.9 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.50 (t,J=7.8 Hz, 1H), 7.43-7.33 (m, 3H), 7.26-7.13 (m, 3H), 5.11 (dd, J=4.9,13.2 Hz, 1H), 4.50-4.34 (m, 4H), 4.33-4.23 (m, 2H), 3.00-2.87 (m, 1H),2.83-2.70 (br s, 2H), 2.67-2.55 (m, 1H), 2.45-2.25 (m, 7H), 2.05-1.94(m, 1H).

Example 97N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-isopropylpyridin-2-yl)acetamide

A. 5-(Prop-1-en-2-yl)pyridin-2-amine

To a stirred and degassed solution of 5-bromopyridin-2-amine (3.5 g,20.34 mmol) in 1,4-dioxane.water (1:1, 40 mL) was added potassiumphosphate (12.94 g, 61.04 mmol), and continued degassing for 10 min.Then, 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (5.21g, 30.51 mmol) followed by [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (1.47 mg, 2.014 mmol) was added, degassed 10 minwith stirring and heated to 100° C. for 2 h. The reaction mixture wascooled to room temperature, filtered through the Celite pad. To thefiltrate was added cold water and extracted with ethyl acetate (3×200mL). The organic layers were washed with water (2×100 mL), brine (100mL), dried over sodium sulphate and concentrated. The resultant residuewas purified by silicagel (100-200 mesh) column chromatography using 40%of ethylacetate in petroleum ether to afford 5-(prop-1-en-2-yl)pyridin-2-amine (2.5 g, 18.65 mmol, 91% yield) as brown colored solid.MS (ESI) m/z 135.18 [M+1]⁺.

B. 5-Isopropylpyridin-2-amine

To slurry of 20% palladium hydroxide (1 g) in ethyl acetate (50 mL) wasadded 5-(prop-1-en-2-yl) pyridin-2-amine (2.5 g, 18.65 mmol) and stirredat room temperature for 2 h under hydrogen balloon (1 atm). The reactionmixture was filtered through Celite pad, dried over sodium sulphate andconcentrated to afford the 5-isopropylpyridin-2-amine (2 g, 14.70 mmol,79% yield) as a brown liquid. MS (ESI) m/z 137.15 [M+1]⁺.

C. 2-Bromo-5-isopropylpyridine

To a cold (0° C.) stirred solution of 5-isopropylpyridin-2-amine (2 g,14.70 mmol) in 47% aqueous hydrobromic acid (20 mL) was added a solutionof sodium nitrite (2.63 g, 38.23 mmol, in 5 mL water) and stirred at thesame temperature for 30 min. To this reaction mixture bromine (2.27 mL,44.1 mmol) was drop wise at −5° C. and stirred at room temperature for 4h. The reaction mixture was neutralized with aqueous sodium hydroxidesolution and extracted with dichloromethane (2×50 mL). The combinedorganic layers were washed with saturated aqueous sodium thiosulphatesolution (100 mL), brine (50 mL), dried over sodium sulphate andconcentrated to afford 2-bromo-5-isopropylpyridine (1.8 g, 9.04 mmol,62% yield) as a brown colored liquid. MS (ESI) (m/z) 200.23 [M+1]⁺.

D. 2-Iodo-5-isopropylpyridine

To a stirred solution of 2-bromo-5-isopropylpyridine (1.8 g, 9.04 mmol)in acetonitrile (20 mL) was added potassium iodide (3.75 g, 22.61 mmol)and acetyl chloride (1.42 g, 18.08 mmol) at room temperature and stirredat 85° C. for 16 h. The reaction mixture was neutralized with aqueoussodium bicarbonate solution and extracted with dichloromethane (2×50mL). The combined organic layers were washed with saturated aqueoussodium thiosulphate solution (100 mL) brine (50 mL) and dried oversodium sulphate and concentrated. The resultant residue was purified bySilicagel (100-200 mesh) column chromatography using 5% of ethylacetatein pet.ether as eluent to afford 2-bromo-5-isopropylpyridine (850 mg,3.44 mmol, 39% yield). MS (ESI) (m/z) 248.24 [M+1]⁺.

E. Ethyl 2,2-difluoro-2-(5-isopropylpyridin-2-yl)acetate

To a stirred solution of 2-iodo-5-isopropylpyridine (800 mg, 3.23 mmol)in dimethyl sulfoxide (15 mL) was added ethyl2-bromo-2,2-difluoroacetate (0.62 mL, 4.845 mmol) followed by copper(534 g, 8.39 mmol) and stirred for 16 h at 50° C. The reaction mixturewas neutralized with aqueous saturated ammonium chloride solution andextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with water (2×50 mL), brine (50 mL), dried over sodiumsulphate and concentrated to afford ethyl2,2-difluoro-2-(5-isopropylpyridin-2-yl)acetate (650 mg, 2.67 mmol, 82%)as a brown liquid. MS (ESI) m/z 244.28 [M+1]⁺.

F. Ethyl 2,2-difluoro-2-(5-isopropylpyridin-2-yl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(5-isopropylpyridin-2-yl)acetate (600 mg, 2.46 mmol) inin methanol/tetrahydrofuran/water mixture (9 mL, 1:1:1) was addedlithium hydroxide monohydrate (310 mg, 7.40 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous potassium bisulphate (10 mL)and extracted with ethyl acetate (2×50 mL). The combined organic layerswere washed with brine (20 mL), dried over sodium sulphate andconcentrated to afford ethyl2,2-difluoro-2-(5-isopropylpyridin-2-yl)acetic acid (450 mg, 2.09 mmol,85% yield) as a brown semi solid. MS (ESI) m/z 216.30 [M−1]⁺.

G.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-isopropylpyridin-2-yl)acetamide

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(5-isopropylpyridin-2-yl)aceticacid (333 mg, 1.54 mmol)in pyridine (10 mL) was added phosphoryl chloride (0.4 mL, 3.87 mmol)drop wise and stirred at 0-5° C. for 30 min. To this was added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (400 mg, 1.29 mmol) and stirred at room temperature for 2h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×50 mL), brine (50 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by column chromatography using 3-4% of methanol indichloromethane as a eluent to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-isopropylpyridin-2-yl)acetamide(65 mg, 0.138 mmol, 11% yield) as an off-white solid. MS (ESI) m/z471.10 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.99 (s, 1H), 9.61 (brt, J=6.05 Hz, 1H), 8.62 (s, 1H), 7.91 (dd, J=8.07, 1.83 Hz, 1H), 7.71(d, J=8.07 Hz, 2H), 7.52 (s, 1H), 7.46 (br d, J=7.70 Hz, 1H), 5.11 (brdd, J=13.57, 5.14 Hz, 1H), 4.55-4.27 (m, 4H), 3.10-3.00 (m, 1H),2.95-2.85 (m, 1H), 2.75-2.67-2.54 (m, 1H), 2.44-2.30 (m, 1H), 2.07-1.93(m, 1H), 1.30-1.20 (m, 6H).

Example 98N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(methylsulfonyl)ethoxy)phenyl)acetamide

A. (2-(3-Iodophenoxy)ethyl)(methyl)sulfane

To a stirred solution of 3-iodophenol (5 g, 22.72 mmol) intetrahydrofuran (60 mL) was added diisopropyl azodicarboxylate (8.9 mL,45.45 mmol) followed by triphenylphosphine (11.9 g, 45.45 mmol) and2-(methylthio)ethanol (1.97 mL, 22.72 mmol) at 0° C. and stirred at roomtemperature for 3 h. The reaction mixture was quenched with ice water(50 mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with water (50 mL), brine (50 mL), dried over sodiumsulfate, filtered and concentrated. The obtained crude was purified byflash chromatography (1% ethyl acetate in pet ether) to afford(2-(3-Iodophenoxy)ethyl)(methyl)sulfane (2.5 g, 8.503 mmol, 37% yield)as a colorless liquid. ¹H NMR (300 MHz, DMSO-d₆) δ (ppm) 7.33-7.24 (m,1H), 7.04-6.95 (m, 1H), 6.90-6.83 (m, 1H), 4.12 (t, J=6.8 Hz, 1H), 2.87(t, J=6.8 Hz, 1H), 2.21 (s, 1H).

B. 1-Iodo-3-(2-(methylsulfonyl)ethoxy)benzene

To a stirred solution of (2-(3-Iodophenoxy)ethyl)(methyl)sulfane (2.5 g,8.503 mmol) in dichloromethane (25 mL) was added m-chloroperbenzoicacid(4.4 g, 25.5 mmol) at 0° C. and stirred at room temperature for 3 h. Thereaction mixture was basified with aq.NaHCO₃ (200 mL) and extracted withdichloromethane (3×50 mL), washed with brine (50 mL) and dried oversodium sulphate, organic phase was concentrated. Obtained residue waspurified by column chromatography (100-200 silica) using 5% ethylacetate in hexanes to give the1-iodo-3-(2-(methylsulfonyl)ethoxy)benzene (1.2 g, 3.68 mmol, 43% yield)as an off white solid. MS (ESI) m/z 349.26 [M+Na]⁺.

C. Ethyl 2,2-difluoro-2-(3-(2-(methylsulfonyl)ethoxy)phenyl)acetate

To a stirred solution of 1-iodo-3-(2-(methylsulfonyl)ethoxy)benzene (1.2g, 3.68 mmol) in dimethyl sulfoxide (12 mL) was added copper (708 mg,11.04 mmol) and ethyl 2-iodo-2,2-difluoroacetate (1.1 g, 4.42 mmol) atroom temperature and stirred at room temperature for 16 h. To thereaction mixture was added aqueous saturated ammonium chloride (50 mL)solution and extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with water (2×100 mL), brine (100 mL), driedover sodium sulphate and concentrated to afford ethyl2,2-difluoro-2-(3-(2-(methylsulfonyl)ethoxy)phenyl)acetate (720 mg, 2.23mmol, 61% yield). MS (ESI) m/z 345.4 [M+Na]⁺.

D. 2,2-Difluoro-2-(3-(2-(methylsulfonyl)ethoxy)phenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(3-(2-(methylsulfonyl)ethoxy)phenyl)acetate (720 mg, 2.23mmol) in 1,4-dioxane (30 mL) was added 4M aqueous hydrochloric acid (15mL) at room temperature and stirred at room temperature for 16 h. Thereaction mixture was extracted with ethyl acetate (3×50 mL), washed withbrine (50 mL) and dried over sodium sulphate, organic phase wasconcentrated to give the2,2-difluoro-2-(3-(2-(methylsulfonyl)ethoxy)phenyl)acetic acid (550 mg,1.87 mmol, 84% yield) as an off white solid. MS (ESI) m/z 293.21 [M+H]⁺.

E.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(methylsulfonyl)ethoxy)phenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(3-(2-(methylsulfonyl)ethoxy)phenyl)acetic acid (250 mg,0.85 mmol) in pyridine (10 mL) was added phosphoryl chloride (0.2 mL,2.55 mmol) drop wise and stirred at 0° C. for 1 h and then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (394 mg, 1.02 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×50 mL), brine (50 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase column chromatography using50-55% acetonitrile in aqueous formic acid (0.1%) to giveN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(methylsulfonyl)ethoxy)phenyl)acetamide(50 mg, 0.091 mmol, 11% yield) as a white solid. MS (ESI) m/z 549.81[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ (ppm) 10.98 (s, 1H), 9.63 (br t,J=5.9 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.52-7.44 (m, 1H), 7.41-7.34 (m,2H), 7.23-7.13 (m, 3H), 5.10 (dd, J=5.1, 13.5 Hz, 1H), 4.45 (br d, J=6.4Hz, 2H), 4.40-4.22 (m, 4H), 3.64 (t, J=5.4 Hz, 1H), 2.97-2.84 (m, 1H),2.63-2.57 (m, 1H), 2.44-2.33 (m, 1H), 2.04-1.95 (m, 1H).

Example 99N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(3-(methylsulfonyl)propyl)phenyl)acetamide

A. Ethyl 2,2-difluoro-2-(3-formylphenyl)acetate

To a stirred solution of 3-iodobenzaldehyde (4 g, 17.24 mmol) indimethylsulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate(5.25 g, 25.86 mmol) followed by copper powder (2.84 g, 44.82 mmol) atroom temperature and stirred at 60° C. for 5 h. The reaction mixture wasbasified with aqueous saturated sodium bicarbonate solution andextracted with ethyl acetate (3×40 mL). The combined organic layers werewashed with water (40 mL), brine (40 mL), dried over sodium sulfate,filtered and solvent was concentrated and obtained crude was purified byflash column chromatography (20% ethyl acetate in pet ether) to affordethyl 2,2-difluoro-2-(3-formylphenyl)acetate (2.3 g, 8.27 mmol, 58%) asa colorless liquid. MS (ESI) m/z 228.1 [M]⁺.

B. Ethyl 2,2-difluoro-2-(3-vinylphenyl)acetate

To a stirred solution of methyltriphenylphosphonium bromide (1.58 g, 4.4mmol) in tetrahydrofuran/diethyl ether mixture (30 mL, 2:1), was addedn-butyl lithium (1 mL, 2.49 mmol) at −78° C. and stirred the sametemperature for 30 min. Then, ethyl2,2-difluoro-2-(3-formylphenyl)acetate (0.5 g, 2.27 mmol) was added intothe reaction mixture at −78° C. and stirred at 0° C. for 3 h. Thereaction mixture was quenched with aqueous saturated ammonium chloridesolution and extracted with ethyl acetate (3×20 mL). The combinedorganic layers were washed with water (20 mL), brine (20 mL), dried oversodium sulfate, filtered and solvent was concentrated and obtained crudewas purified by flash column chromatography (20% ethyl acetate in petether) to afford ethyl 2,2-difluoro-2-(3-vinylphenyl)acetate (0.32 g,1.41 mmol, 64% yield) as a colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ7.63 (s, 1H), 7.53-7.48 (m, 2H), 7.42 (d, J=7.6 Hz, 1H), 6.73 (dd,J=17.6, 10.4 Hz, 1H), 5.81 (d, J=17.6 Hz, 1H), 5.33 (d, J=10.8 Hz, 1H),4.30 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H).

C. 3-(Methylsulfonyl)prop-1-ene

To a stirred solution of allyl(methyl)sulfane (5 g, 56.81 mmol) indichloromethane (50 mL) was added meta-chloroperoxybenzoic acid (19.65g, 113.63 mmol) at 0° C. and stirred at room temperature for 16 h. Thereaction mixture was basified with saturated sodium bicarbonate solutionand extracted with dichloro methane (3×50 mL). The combined organiclayers were washed with water (40 mL), brine (40 mL), dried over sodiumsulfate, filtered and concentrated. The obtained crude was purified byflash column chromatography (20% ethyl acetate in pet ether) to afford3-(methylsulfonyl)prop-1-ene (2.5 g, 20.83 mmol, 36% yield) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 5.98 (ddt, J=17.2, 14.8, 7.2 Hz, 1H),5.48 (dd, J=17.2, 1.2 Hz, 2H), 3.74 (d, J=7.6 Hz, 2H), 2.88 (s, 3H).

D. (E)-Ethyl2,2-difluoro-2-(3-(3-(methylsulfonyl)prop-1-enyl)phenyl)acetate

To a stirred solution of ethyl 2,2-difluoro-2-(3-vinylphenyl)acetate(100 mg, 0.44 mmol) in dichloromethane (10 mL) was added3-(methylsulfonyl)prop-1-ene (265 mg, 2.21 mmol) followed by Grubbs' IIgeneration catalyst (19 mg, 0.02 mmol) at room temperature and refluxedat 40° C. for 16 h. The volatiles were remove under reduced pressure andobtained residue was purified by flash column chromatography (30% ethylacetate in pet ether) to afford (E)-ethyl2,2-difluoro-2-(3-(3-(methylsulfonyl)prop-1-enyl)phenyl)acetate (60 mg,0.18 mmol, 42% yield) as a colorless liquid. ¹H NMR (300 MHz, CDCl₃) δ7.64 (s, 1H), 7.59-7.42 (m, 3H), 6.76 (d, J=16.2 Hz, 1H), 6.41-6.31 (m,1H), 4.31 (q, J=6.9 Hz, 2H), 3.91 (d, J=7.2 Hz, 2H), 2.92 (s, 3H), 1.31(t, J=6.9 Hz, 3H).

E. Ethyl 2,2-difluoro-2-(3-(3-(methylsulfonyl)propyl)phenyl)acetate

To a stirred solution of (E)-ethyl2,2-difluoro-2-(3-(3-(methylsulfonyl)prop-1-enyl)phenyl)acetate (220 mg,0.69 mmol) in ethyl acetate (10 mL) was added slurry of 10% palladiumhydroxide (50 mg) in ethyl acetate under nitrogen stream. The reactionmixture was stirred under hydrogen balloon pressure at room temperaturefor 16 h. The hydrogen atmosphere was evacuated and reaction mixture wasfiltered through a Celite pad, filtrated and concentrated obtainedresidue was purified by flash column chromatography (20% ethyl acetatein pet ether) to afford ethyl2,2-difluoro-2-(3-(3-(methylsulfonyl)propyl)phenyl)acetate (120 mg, 0.37mmol, 54% yield) as a colorless liquid. ¹H NMR (300 MHz, CDCl₃) δ 7.48(d, J=7.8 Hz, 1H), 7.43 (s, 1H), 7.39 (d, J=7.5 Hz, 1H), 7.32 (dd,J=8.1, 7.9 Hz, 1H), 4.31 (q, J=6.9 Hz, 2H), 2.99 (t, J=7.5 Hz, 2H), 2.89(s, 3H), 2.66 (t, J=7.5 Hz, 2H), 2.23-2.15 (m, 2H), 1.32 (t, J=6.9 Hz,3H).

F. 2,2-Difluoro-2-(3-(3-(methylsulfonyl)propyl)phenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(3-(3-(methylsulfonyl)propyl)phenyl)acetate (150 mg, 0.47mmol) in tetrahydrofuran:methanol:water mixture (10 mL, 1:1:1) was addedlithium hydroxide monohydrate (59 mg, 1.41 mmol) and stirred at roomtemperature for 4 h. The volatiles were removed under reduced pressureand the obtained crude product was dissolved in water (15 mL), washedwith ethyl acetate (2×6 mL). The aqueous layer was acidified with 1Nhydrochloride aqueous solution and extracted with ethyl acetate (3×8mL). The combined organic layers were washed with brine (8 mL), driedover sodium sulfate, filtered and concentrated to afford2,2-difluoro-2-(3-(3-(methylsulfonyl)propyl)phenyl)acetic acid (130 mg,0.44 mmol, 94% yield) as semi-solid compound. ¹H NMR (300 MHz, DMSO-d₆)δ 7.50-7.41 (m, 4H), 3.32 (brs, 1H), 3.12-3.09 (m, 2H), 3.04 (s, 3H),2.78 (t, J=7.8 Hz, 2H), 2.04-1.96 (m, 2H).

G.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(3-(methylsulfonyl)propyl)phenyl)acetamide

To an ice cold solution of3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (180 mg, 0.58 mmol) and2,2-difluoro-2-(3-(3-(methylsulfonyl)propyl)phenyl)acetic acid (136 mg,0.46 mmol) in N,N-dimethylformamide (10 mL) was addedN,N-diisopropylethylamine (0.3 mL, 1.74 mmol) followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (442 mg, 1.16 mmol) and stirred at roomtemperature for 4 h. The reaction mixture was diluted with water (15 mL)and extracted with ethyl acetate (3×10 mL). The combined organic layerswere washed with brine (10 mL), dried over sodium sulphate, filtered andconcentrated. The obtained crude product was purified by Reveleris C-18reversed phase column (50% acetonitrile in 0.1% aqueous formic acid) toaffordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(3-(methylsulfonyl)propyl)phenyl)acetamide(40 mg, 0.07 mmol, 12% yield) as an off-white solid. MS (ESI) m/z 472.11[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.63 (t, J=5.6 Hz,1H), 7.68 (d, J=7.8 Hz, 1H), 7.44-7.36 (m, 6H), 5.10 (dd, J=13.2, 5.1Hz, 1H), 4.45 (d, J=5.1 Hz, 2H), 4.42 (d, J=17.9 Hz, 1H), 4.28 (d,J=17.7, 1H), 3.11 (t, J=8.1 Hz, 2H), 2.96 (s, 3H), 2.91-2.85 (m, 1H),2.76 (t, J=7.8 Hz, 2H), 2.67-2.55 (m, 1H), 2.45-2.30 (m, 1H), 2.06-1.92(m, 3H).

Example 100N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(2-fluoropropan-2-yl)phenyl)acetamide

A.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(2-fluoropropan-2-yl)phenyl)acetamide

To a cold (0° C.) stirred solution ofN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(2-hydroxypropan-2-yl)phenyl)acetamide(170 mg, 0.35 mmol) in dichloromethane (20 mL) was addeddiethylaminosulfur trifluoride (0.06 mL, 0.52 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was diluted with saturatedsodium bicarbonate solution (20 mL) and extracted with ethyl acetate(2×25 mL). The combined organic layer was washed with brine (20 mL),dried over sodium sulphate and concentrated. The product was purified byReveleris C-18 reversed phase column using 65% acetonitrile in aqueousformic acid (0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(2-fluoropropan-2-yl)phenyl)acetamide(70 mg, 0.16 mmol, 41% yield) as an off-white solid. MS (ESI) m/z 486.23[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.65 (br t, J=6.1 Hz,1H), 7.68 (d, J=7.8 Hz, 1H), 7.64-7.54 (m, 1H), 7.40-7.38 (m, 4H),7.37-7.32 (d, J=8.3 Hz, 2H), 5.10 (br dd, J=5.1, 13.4 Hz, 1H), 4.54-4.38(m, 3H), 4.31-4.23 (m, 1H), 2.99-2.84 (m, 1H), 2.69-2.55 (m, 1H),2.43-2.29 (m, 1H), 2.05-1.93 (m, 1H), 1.69 (s, 3H), 1.63 (s, 3H).

Example 1012-(1-Benzyl-6-oxo-1,6-dihydropyridin-3-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. 1-Benzyl-5-iodopyridin-2(1H)-one

To a stirred solution of 5-iodopyridin-2-ol (5 g, 22.62 mmol) in dryN,N-dimethylformamide (50 mL) was added potassium carbonate (9.36 g,67.86 mmol) followed by benzylbromide (2.95 mL, 24.88 mmol) at roomtemperature and stirred at 70° C. for 4 h. The reaction mixture wasquenched with water (100 mL) and extracted with ethyl acetate (2×100mL). The combined organic layers were washed with brine (50 mL), driedover sodium sulphate and concentrated. The resultant residue waspurified by column chromatography (100-200 silica) using 30%ethylacetate in hexanes as elunt to afford1-benzyl-5-iodopyridin-2(1H)-one (4.5 g, 14.46 mmol, 64% yield) as anoff white solid. MS (ESI) m/z 311.98 [M+1]⁺.

B. 5-Acetyl-1-benzylpyridin-2(1H)-one

To a stirred solution of 1-benzyl-5-iodopyridin-2(1H)-one (1.2 g, 3.858mmol) in N,N-dimethylformamide (12 mL) was added 1-(vinyloxy)butane(1.93 g, 19.29 mmol) followed by 3M aqueous potassium carbonate (2.4 mL,11.57 mmol), Pd(OAc)₂ (400 mg, 0.192 mmol) was added followed by 1,3-bis (diphenylphosphino) propane (477 mg, 1.157 mmol) and stirred at80° C. for 3 h. The reaction mixture was cooled to room temperature and1N aqueous hydrochloric acid (12 mL) was added and stirred at 40° C. for2 h. The reaction mixture was cooled to room temperature and water (40mL) was added and extracted with ethyl acetate (3×50 mL), washed withwater (2×50 mL), brine (50 mL) and dried over sodium sulphate, organicphase was concentrated. Obtained residue was purified by columnchromatography (100-200 silica) using 30% ethyl acetate in hexanes togive the 5-acetyl-1-benzylpyridin-2(1H)-one (700 mg, 3.08 mmol, 80%yield) as yellow syrup. MS (ESI) m/z 228.24 [M+H]⁺.

C. Ethyl 2-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-2-oxoacetate

To a stirred solution of 5-acetyl-1-benzylpyridin-2(1H)-one (700 mg,3.08 mmol) in pyridine (7 mL) was added selenium dioxide (855 mg, 7.709mmol) and stirred at 100° C. for 3 h. The reaction mixture was dilutedwith dichloromethane (14 mL) and filtered through celite pad. To thefiltrate was added ethylchloroformate (2.1 mL) at 0° C. and stirred atroom temperature for 16 h. The reaction mixture was neutralized with 1Naqueous hydrochloric acid (up to pH-4) and extracted with ethyl acetate(2×50 mL). The combined organic layer was washed with water (2×50 mL),brine (50 mL) and dried over sodium sulphate and was concentrated togive ethyl 2-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-2-oxoacetate (500mg, 1.75 mmol, 57% yield) as yellow syrup. MS (ESI) m/z 286.12 [M+H]⁺.

D. Ethyl 2-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-2,2-difluoroacetate

To ethyl 2-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-2-oxoacetate (500mg, 1.75 mmol) was added diethyl amino sulfur trifluoride (1.5 mL) at 0°C. and stirred at room temperature for 16 h. The reaction mixture wasneutralized with aqueous saturated sodium bicarbonate (up to pH-8) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×25 mL), brine (25 mL), dried over sodium sulphateand concentrated to afford ethyl2-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-2,2-difluoroacetate (450 mg,1.46 mmol, 84% yield). MS (ESI) m/z 265.07 [M+1]⁺.

E. 2-(1-Benzyl-6-oxo-1,6-dihydropyridin-3-yl)-2,2-difluoroacetic acid

To a stirred solution of ethyl2-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-2,2-difluoroacetate (400 mg,1.302 mmol) in tetrahydrofuran:methanol:water mixture (10 mL, 1:1:1) wasadded lithium hydroxide monohydrate (112 mg, 3.906 mmol) and stirred atroom temperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with saturated potassium bisulphate (20 mL) andextracted with ethyl acetate (2×25 mL). The combined organic layers werewashed with brine (25 mL), dried over sodium sulphate and concentratedto afford 2-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-2,2-difluoroaceticacid (350 mg, 1.254 mmol, 96% yield). MS (ESI) m/z 280.32 [M+1]⁺.

F.2-(1-Benzyl-6-oxo-1,6-dihydropyridin-3-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a cold (0° C.) stirred solution of2-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-2,2-difluoroacetic acid (279mg, 1.294 mmol) in pyridine (10 mL) was added phosphoryl chloride (0.36mL, 3.894 mmol) drop wise and stirred at 0° C. for 1 h and then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (400 mg, 1.294 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×50 mL), brine (50 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase column chromatography using50-55% acetonitrile in aqueous formic acid (0.1%) to afford2-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(80 mg, 0.148 mmol, 11% yield) as an off white solid. MS (ESI) m/z535.09 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ (ppm) 10.99 (s, 1H), 9.62 (brt, J=5.9 Hz, 1H), 8.18 (br s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.56 (dd,J=2.7, 9.5 Hz, 1H), 7.44 (s, 1H), 7.40-7.24 (m, 6H), 5.16 (s, 1H), 5.10(br dd, J=4.9, 13.2 Hz, 1H), 4.46 (br d, J=5.9 Hz, 1H), 4.41 (br d,J=17.6 Hz, 1H), 4.27 (br d, J=17.6 Hz, 1H), 2.97-2.85 (m, 1H), 2.69-2.56(m, 1H), 2.43-2.30 (m, 1H), 2.02-1.98 (m, 1H).

Example 102N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-methoxypyridin-2-yl)acetamide

A. 2-Iodo-5-methoxypyridine

To a stirred solution of 2-bromo-5-methoxypyridine (2 g, 10.63 mmol) in1,4-dioxane (20 mL) was added sodium iodide (3.3 g, 21.27 mmol), copperiodide (100 mg, 0.53 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine(150 mg, 1.16 mmol) at room temperature and stirred at 110° C. for 16 hin sealed tube. The reaction mixture was quenched with water (20 mL) andextracted with ethyl acetate (3×20 mL). The combined organic layers werewashed with water (2×10 mL), brine (10 mL), dried over sodium sulphateand concentrated to afford 2-iodo-5-methoxypyridine (1.1 g, 4.46 mmol,47% yield) as brown liquid. GCMS (m/z) 235.0 [M]⁺.

B. Ethyl 2,2-difluoro-2-(5-methoxypyridin-2-yl)acetate

To a stirred solution of 2-iodo-5-methoxypyridine (1 g, 4.32 mmol) indimethyl sulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate(1.1 mL, 8.65 mmol), copper (0.73 g, 11.20 mmol) and stirred for 16 h at50° C. The reaction mixture was neutralized with aqueous saturatedammonium chloride solution and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with water (2×10 mL), brine (10mL), dried over sodium sulphate and concentrated to afford ethyl2,2-difluoro-2-(5-methoxypyridin-2-yl)acetate (700 mg, 3.03 mmol, 71%)as a brown liquid. GCMS (m/z) 231.1.

C. 2,2-Difluoro-2-(5-methoxypyridin-2-yl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(5-methoxypyridin-2-yl)acetate (600 mg, 2.59 mmol) inethanol/tetrahydrofuran/water mixture (9 mL, 1:1:1) was added lithiumhydroxide monohydrate (327 mg, 7.79 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous potassium bisulphate (10 mL)and extracted with ethyl acetate (2×30 mL). The combined organic layerswere washed with brine (10 mL), dried over sodium sulphate andconcentrated to afford 2,2-difluoro-2-(5-methoxypyridin-2-yl)acetic acid(450 mg, 2.21 mmol, 85% yield) as a brown semi solid. MS (ESI) m/z204.23 [M+1]⁺.

D.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-methoxypyridin-2-yl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(5-methoxypyridin-2-yl)acetic acid (300 mg, 1.47 mmol)and 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (360 mg, 1.18 mmol) in N,N-dimethylformamide (20 mL) wasadded N,N-diisopropylethylamine (0.8 mL, 2.20 mmol) followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (670 mg, 4.41 mmol) and stirred at roomtemperature for 16 h. The reaction mixture was diluted with water (70mL) and extracted with ethyl acetate (2×20 mL). The combined organiclayers were washed with brine (30 mL), dried over sodium sulphate andconcentrated. The resultant residue was purified by Reveleris C-18reversed phase column using 57% acetonitrile in aqueous formic acid(0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-methoxypyridin-2-yl)acetamide(58 mg, 0.12 mmol, 8% yield) as an off-white solid. MS (ESI) m/z 459.20[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.61-9.53 (m, 1H),8.41 (br d, J=2.9 Hz, 1H), 7.72 (dd, J=8.3, 11.2 Hz, 2H), 7.57 (dd,J=2.9, 8.8 Hz, 1H), 7.52 (s, 1H), 7.45 (br d, J=8.3 Hz, 1H), 5.11 (brdd, J=4.9, 13.2 Hz, 1H), 4.53-4.27 (m, 4H), 3.89 (s, 3H) 2.98-2.85 (m,1H), 2.69-2.56 (m, 1H), 2.44-2.31 (m, 1H), 2.06-1.95 (m, 1H).

Example 103N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetamide

A. 6-Hydroxy-N-methoxy-N-methylnicotinamide

To a stirred solution of 6-hydroxynicotinic acid (10 g, 45.24 mmol) intetrahydrofuran (100 mL) was added EDC.HCl (13.01 g, 67.87 mmol), HOBT(10.39 g, 67.87 mmol), N,O-dimethyl hydroxylamine HCl (5.29 g, 67.87mmol), N,N-diisopropylethylamine (31.55 mL, 180.99 mmol) sequentiallyand stirred at room temperature for 16 h. The reaction mixture wasdiluted with water (100 mL) and extracted with ethyl acetate (3×500 mL).The combined organic layers were washed with brine (50 mL), dried oversodium sulphate and concentrated. The resultant residue was purified bycolumn chromatography (100-200 silica) using 5% methanol:dichloromethaneto afford 6-hydroxy-N-methoxy-N-methylnicotinamide (8 g, 43.95 mmol, 96%yield). LCMS (ESI) m/z 183.0 [M+1]⁺.

B. N-Methoxy-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

To a stirred solution of 6-hydroxy-N-methoxy-N-methylnicotinamide (8 g,43.95 mmol) in N,N-dimethylformamide was added methyl iodide (3.01 mL,48.35 mmol), potassium carbonate (18.19 g, 131.86 mmol) at roomtemperature and stirred for 3 h. The reaction mixture was diluted withwater (100 mL) and extracted with ethyl acetate (3×500 mL). The combinedorganic layers were washed with brine (50 mL), dried over sodiumsulphate and concentrated. The resultant residue was purified by columnchromatography (100-200 silica) using 4% methanol:dichloromethane toafford N-methoxy-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (6g, 30.61 mmol, 69% yield). LCMS (ESI) m/z 197.29 [M+1]⁺.

C. 5-Acetyl-1-methylpyridin-2(1H)-one

To a stirred solution ofN-methoxy-N,1-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (6 g,30.61 mmol) in dry tetrahydrofuran (50 mL) was added methyl lithium 1.6M in diethyl ether (2.67 mL), at 0° C. for 3 h. The reaction mixture wasquenched with saturated ammonium chloride solution and extracted withethyl acetate (2×500 mL). The combined organic layers were washed withbrine (50 mL), dried over sodium sulphate and concentrated The resultantresidue was purified by column chromatography (100-200 silica) using7-10% methanol:dichloromethane to afford5-acetyl-1-methylpyridin-2(1H)-one (4 g, 26.49 mmol, 86% yield). MS(ESI) m/z 152.14 [M+1]⁺.

D. Ethyl 2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-oxoacetate

To a stirred solution of 5-acetyl-1-methylpyridin-2(1H)-one (4 g, 26.49mmol) in pyridine (50 mL) was added selenium dioxide (7.35 g, 66.22mmol) and stirred for 16 h at 100° C. The reaction mixture was dilutedwith dichloromethane (50 mL) and filtered through Celite pad. To thefiltrate was added ethyl chloroformate (12 mL) at 0° C. and stirred for2 h. To the resultant reaction mixture was added water (30 mL) andextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with water (2×100 mL), brine (100 mL), dried over sodiumsulphate and concentrated. The resultant residue was purified by columnchromatography (100-200 silica) using 15-20% ethyl acetate in pet etherto afford ethyl 2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-oxoacetate(2 g, 9.56 mmol, 36% yield). LCMS (ESI) m/z 210.29 [M+1]⁺.

E. Ethyl 2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetate

To ethyl 2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-oxoacetate (2 g,9.56 mmol) was added diethylaminosulfur trifluoride (3.2 mL, 23.92 mmol)and stirred for 12 h at room temperature. The reaction mixture wasneutralized with aqueous saturated sodium bicarbonate (up to pH-8) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×10 mL), brine (10 mL), dried over sodium sulphateand concentrated to afford ethyl2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetate (1 g,4.32 mmol, 45%) as a liquid. LCMS (ESI) m/z 232.33[M+1]⁺.

F. 2,2-Difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetate (1 g,4.32 mmol) in tetrahydrofuran:Methanol:water mixture (30 mL, 1:1:1) wasadded lithium hydroxide (0.909 g, 21.64 mmol) and stirred at roomtemperature for 6 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous hydrochloric acid (10 mL) andextracted with ethyl acetate (2×20 mL). The combined organic layers werewashed with brine (20 mL), dried over sodium sulphate and concentratedto afford 2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)aceticacid (500 g, 2.46 mmol, 56% yield) as off white solid. LCMS (ESI) m/z204.35 [M+1]⁺.

G.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetic acid(196.6 mg, 0.968 mmol) in pyridine was added phosphoryl chloride (0.27mL, 2.906 mmol) dropwise and stirred at 0-5° C. for 1 h. To thisreaction mixture was added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.968 mmol) and stirred at room temperature for30 min. The reaction mixture was neutralized with aqueous saturatedsodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with water (2×10 mL), brine(10 mL), dried over sodium sulphate and concentrated. The resultantresidue was purified by Reveleris C-18 reversed phase Grace columnchromatography using 40-60% acetonitrile in aqueous formic acid (0.1%)to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetamide(60 mg, 0.131 mmol, 13% yield) as an off white solid. MS (ESI) m/z459.16 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.98 (s, 1H), 9.58 (brt, J=5.85 Hz, 1H), 8.05 (s, 1H), 7.70 (d, J=7.68 Hz, 1H), 7.58-7.35 (m,3H), 6.49 (d, J=9.50 Hz, 1H), 5.11 (dd, J=13.16, 5.12 Hz, 1H), 4.5-4.35(m, 3H), 4.35-4.25 (d, 1H), 3.53-3.45 (s, 3H), 2.98-2.82 (m, 1H),2.67-2.52 (m, 1H), 2.45-2.30 (m, 1H), 2.05-1.95 (m, 1H).

Example 1042-(5-Tert-butylpyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. tert-Butyl 5-bromopyridin-2-ylcarbamate

To a cold (0° C.) stirred solution of 5-bromopyridin-2-amine (20 g,116.30 mmol) in dichloromethane (200 mL) was added triethylamine (34 mL,255.87 mmol), di-tert-butyl dicarbonate (35 mL, 151.19 mmol) followed by4-dimethylaminopyridine (1.4 g, 11.63 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was quenched with water andextracted with dichloromethane (2×200 mL). The combined organic layerswere washed with water (200 mL), brine (200 mL), dried over sodiumsulfate and concentrated. The resultant residue was purified by columnchromatography with 5% ethyl acetate in pet ether as eluent to affordtert-butyl 5-bromopyridin-2-ylcarbamate (25.0 g, 91.91 mmol, 79% yield).LCMS (ESI) m/z 219.08 [M+1]⁺.

B. tert-Butyl 5-tert-butylpyridin-2-ylcarbamate

To a cold (−78° C.) stirred solution of copper cyanide (33 g, 367.64mmol) in dry tetrahydrofuran (1200 mL) was added tert-butyl magnesiumchloride (2.0M in tetrahydrofuran) (362 mL, 735.29 mmol) slowly and stirfor 1 h. To this reaction mixture was added tert-butyl5-bromopyridin-2-ylcarbamate (25.0 g, 91.91 mmol) at −78° C., stirredfor 2 h and allowed to stir at room temperature for 16 h. The reactionmixture was quenched with aqueous ammonium chloride solution andextracted with ethyl acetate (3×200 mL). The combined organic layerswere washed with water (200 mL), brine (200 mL), dried over sodiumsulfate and concentrated. The resultant residue was purified by columnchromatography with the eluent of 10% ethyl acetate in pet ether toafford tert-butyl 5-tert-butylpyridin-2-ylcarbamate (15.0 g, 60.00 mmol,65% yield). LCMS (ESI) m/z 251.48 [M+1]⁺.

C. 2-Bromo-5-tert-butylpyridine

To a cold (0° C.) stirred solution of tert-butyl5-tert-butylpyridin-2-ylcarbamate (13.0 g, 52.00 mmol) in aqueoushydrobromic acid (150 mL) was added sodium nitrite (9.3 g, 135.2 mmol)slowly and stir for 15 min. To this reaction mixture was added liquidbromine (8.0 mL, 156.00 mmol) and stirred at room temperature for 4 h.The reaction mixture was quenched with aqueous sodium hydroxide solutionand was extracted with ethyl acetate (3×150 mL). The combined organiclayers were washed with water (100 mL), brine (100 mL), dried oversodium sulfate and concentrated. The resultant residue was purified bycolumn chromatography with the eluent of 5% ethyl acetate in pet etherto afford 2-bromo-5-tert-butylpyridine (3.2 g, 15.02 mmol, 29% yield).LCMS (ESI) m/z 214.11 [M+1]⁺.

D. 5-tert-Butyl-2-iodopyridine

To a stirred solution of 2-bromo-5-tert-butylpyridine (3.2 g, 15.02mmol) in 1,4-dioxane (10 mL) was added sodium iodide (4.5 g, 30.04mmol), copper iodide (145 mg, 0.75 mmol),trans-N,N′-dimethylcyclohexane-1,2-diamine (235 mg, 1.65 mmol) at roomtemperature and stirred at 100° C. for 16 h in sealed tube. The reactionmixture was quenched with water (100 mL) and extracted with ethylacetate (3×100 mL). The combined organic layers were washed with water(2×50 mL), brine (50 mL), dried over sodium sulphate and concentrated toafford 5-tert-butyl-2-iodopyridine (3.5 g, 13.40 mmol, 89% yield). GCMS(m/z) 261.0.

E. Ethyl 2-(5-tert-butylpyridin-2-yl)-2,2-difluoroacetate

To a stirred solution of 5-tert-butyl-2-iodopyridine (3.5 g, 13.40 mmol)in dimethylsulfoxide (30 mL) was added ethyl 2-bromo-2,2-difluoroacetate(5.4 g, 26.81 mmol) followed by copper (2.2 g, 34.86 mmol) and stirredat 55° C. for 5 h. The reaction mixture was quenched with aqueousammonium chloride solution and was extracted with ethyl acetate (3×100mL). The combined organic layers were washed with water (100 mL), brine(100 mL), dried over sodium sulfate, filtered and concentrated to affordethyl 2-(5-tert-butylpyridin-2-yl)-2,2-difluoroacetate (2.8 g, 10.89mmol, 81% yield). LCMS (ESI) m/z 258.17 [M+1]⁺.

F. 2-(5-tert-Butylpyridin-2-yl)-2,2-difluoroacetic acid

To a stirred solution of ethyl2-(5-tert-butylpyridin-2-yl)-2,2-difluoroacetate (2.8 g, 10.89 mmol) inmethanol-tetrahydrofuran-water mixture (15 mL, 1:1:1) was added lithiumhydroxide monohydrate (1.4 g, 32.68 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was diluted with water (50 mL)and acidified with aqueous potassium bisulfate solution and extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith brine (50 mL), dried over sodium sulfate, filtered was concentratedto afford 2-(5-tert-butylpyridin-2-yl)-2,2-difluoroacetic acid (2.0 g,8.73 mmol, 80% yield). LCMS (ESI) m/z 230.32 [M+1]⁺.

G.2-(5-Tert-butylpyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a cold (0° C.) stirred solution of2-(5-tert-butylpyridin-2-yl)-2,2-difluoroacetic acid (2.0 g, 8.73 mmol(300 mg, 1.31 mmol) in pyridine (5 mL) was added phosphoryl chloride(0.4 mL, 3.87 mmol) dropwise and stirred at 0-5° C. for 1 h, and thenadded 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (404 mg, 1.31 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×30 mL), brine (30 mL)and dried over sodium sulphate and was concentrated to afford2-(5-tert-butylpyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(75 mg, 0.15 mmol, 12% yield) as an off white solid. LCMS (ESI) m/z485.17 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ=10.98 (br s, 1H), 9.62 (br t,J=6.1 Hz, 1H), 8.78 (d, J=2.4 Hz, 1H), 8.02 (dd, J=2.4, 8.3 Hz, 1H),7.71 (dd, 8.1 Hz, 1H), 7.52 (s, 1H), 7.46 (d, J=7.8 Hz, 1H), 5.11 (dd,J=4.9, 13.2 Hz, 1H), 4.53-4.28 (m, 4H), 2.99-2.84 (m, 1H), 2.69-2.55 (m,1H), 2.45-2.30 (m, 1H), 2.06-1.94 (m, 1H), 1.35 (s, 9H).

Example 1052-(5-Cyclopropylpyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. 5-Cyclopropylpyridin-2-amine

To a stirred and degassed solution of 5-bromopyridin-2-amine (5 g, 28.90mmol) in 10% water:toluene mixture (100 mL) was added cyclopropylboronicacid (3.73 g, 43.35 mmol) followed by potassium phosphate (12.25 g,57.80 mmol), tricyclohexylphosphine (794 mg, 2.89 mmol) and continueddegassing for 10 min. Then, palladium(II) acetate (650 mg, 2.89 mmol)was added, degassed for additional 10 min and heated at 110° C. for 3 h.The reaction mixture was cooled to room temperature and filtered throughthe Celite pad. To the filtrate was added cold water (100 mL) andextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with water (2×100 mL), brine (100 mL), dried over sodiumsulphate and concentrated to afford 5-cyclopropylpyridin-2-amine (3.0 g,22.39 mmol, 77% yield). GCMS (m/z) 134.1 [M]⁺.

B. 2-Bromo-5-cyclopropylpyridine

To a cold (0° C.) stirred solution of 5-cyclopropylpyridin-2-amine (3.0g, 22.39 mmol) in 47% aqueous hydrobromic acid (25 mL) was added asolution of sodium nitrite (4.0 g, 58.21 mmol) and stirred at the sametemperature for 30 min. To this reaction mixture was then added bromine(10.75 g, 67.16 mmol) and stirred at room temperature for 2 h. Thereaction mixture poured into water (100 mL) and extracted with ethylacetate (3×100 mL). The combined organic layers were washed with brine(100 mL), dried over sodium sulphate and concentrated. The resultantresidue was purified by combi-column chromatography, using 15-20% ethylacetate in pet ether to afford 2-bromo-5-cyclopropylpyridine (1.2 g,6.09 mmol, 27% yield). GCMS (m/z) 197.0 [M]⁺.

C. 5-Cyclopropyl-2-iodopyridine

To a stirred solution of 2-bromo-5-cyclopropylpyridine (1.2 g, 6.09mmol) in 1,4-dioxane (25 mL) was added sodium iodide (1.83 g, 12.18mmol), copper iodide (58 mg, 0.30 mmol),trans-N,N′-dimethylcyclohexane-1,2-diamine (95 mg, 0.67 mmol) at roomtemperature and stirred at 110° C. for 16 h. The reaction mixture wasquenched with water (100 mL) and extracted with ethyl acetate (3×100mL). The combined organic layers were washed with water (2×100 mL),brine (100 mL), dried over sodium sulphate and concentrated to afford5-cyclopropyl-2-iodopyridine (1.2 g, 4.90 mmol, 81%). GCMS (m/z)245.0[M]⁺.

D. Ethyl 2-(5-cyclopropylpyridin-2-yl)-2,2-difluoroacetate

To a stirred solution of 5-cyclopropyl-2-iodopyridine (1.2 g, 4.90 mmol)in dimethyl sulfoxide (12 mL) was added copper (809 mg, 12.73 mmol) andethyl 2-bromo-2,2-difluoroacetate (1.48 g, 7.35 mmol) at roomtemperature and stirred at 55° C. for 2 h. To the reaction mixture wasadded aqueous saturated ammonium chloride (50 mL) solution and extractedwith ethyl acetate (2×100 mL). The combined organic layers were washedwith water (2×100 mL), brine (100 mL), dried over sodium sulphate andconcentrated to afford ethyl2-(5-cyclopropylpyridin-2-yl)-2,2-difluoroacetate (1.0 g, 4.15 mmol,85%). ¹H NMR (400 MHz, CDCl₃) δ 8.44 (br s, 1H), 7.61 (br s, 1H), 7.43(d, J=8.0 Hz, 1H), 4.42-4.30 (m, 2H), 2.04-1.91 (m, 1H), 1.40-1.24 (m,3H), 1.12-1.09 (m, 2H), 0.84-0.77 (m, 2H).

E. 2-(5-Cyclopropylpyridin-2-yl)-2,2-difluoroacetic acid

To a stirred solution of ethyl2-(5-cyclopropylpyridin-2-yl)-2,2-difluoroacetate (1.0 g, 4.15 mmol) intetrahydrofuran:methanol:water mixture (30 mL, 1:1:1) was added lithiumhydroxide monohydrate (523 mg, 12.45 mmol) and stirred at roomtemperature for 4 h. The reaction mixture was concentrated and theresidue was neutralized with saturated potassium bisulphate (25 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine (50 mL), dried over sodium sulphate and concentratedto afford 2-(5-cyclopropylpyridin-2-yl)-2,2-difluoroacetic acid (500 mg,2.35 mmol, 50% yield). MS (ESI) m/z 214.3 [M−1]^(−ve).

F.2-(5-Cyclopropylpyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a cold (0° C.) stirred solution of2-(5-cyclopropylpyridin-2-yl)-2,2-difluoroacetic acid (300 mg, 1.41mmol) in pyridine (20 mL) was added phosphoryl chloride (646 mg, 4.22mmol) dropwise and stirred at 0-5° C. for 30 min. To this reactionmixture was then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (435 mg, 1.41 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (2×100 mL).The combined organic layers were washed with water (100 mL), brine (100mL), dried over sodium sulphate and concentrated. The resultant residuewas purified by Reveleris C-18 reversed phase column chromatographyusing 60-65% acetonitrile in aqueous formic acid (0.1%) to afford2-(5-cyclopropylpyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(140 mg, 0.30 mmol, 21% yield) as an off-white solid. MS (ESI) m/z469.06 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.58 (t, J=6.1Hz, 1H), 8.53 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.66-7.60 (m, 2H), 7.51(s, 1H), 7.46 (d, J=8.3 Hz, 1H), 5.11 (dd, J=4.9, 13.2 Hz, 1H),4.56-4.28 (m, 4H), 3.08-2.85 (m, 1H), 2.67-2.56 (m, 1H), 2.45-2.32 (m,1H), 2.10-1.96 (m, 2H), 1.13-1.03 (m, 2H), 0.89-0.79 (m, 2H).

Example 106N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-isopropoxypyridin-2-yl)acetamide

A. 2-Bromo-5-isopropoxypyridine

To a stirred solution of 6-bromopyridin-3-ol (2 g, 11.49 mmol) inN,N-dimethylformamide (20 mL) was added 2-iodopropane (1.4 mL, 13.79mmol), potassium carbonate (4.7 g, 34.47 mmol) and stirred at 80° C. for6 h. The reaction mixture was quenched with water and extracted withethyl acetate (3×50 mL). The combined organic layers were washed withwater (2×20 mL), brine (20 mL), dried over sodium sulphate andconcentrated to afford 2-bromo-5-isopropoxypyridine (1.4 g, 6.48 mmol,58%) as a pale yellow solid. MS (ESI) m/z 216.20

B. 2-Iodo-5-isopropoxypyridine

To a stirred solution of 2-bromo-5-isopropoxypyridine (1.4 g, 6.48 mmol)in 1,4-dioxane (30 mL) in a sealed tube, was added sodium iodide (1.9 g,12.96 mmol), copper iodide (61 mg, 0.32 mmol),trans-N,N′-dimethylcyclohexane-1,2-diamine (101 mg, 0.71 mmol) at roomtemperature and stirred at 110° C. for 16 h. The reaction mixture wasquenched with water (30 mL) and extracted with ethyl acetate (3×30 mL).The combined organic layers were washed with water (2×20 mL), brine (20mL), dried over sodium sulphate and concentrated to afford2-iodo-5-isopropoxypyridine (1 g, 3.83 mmol, 58% yield) as brown solid.GCMS (m/z) 263.0.

C. Ethyl 2,2-difluoro-2-(5-isopropoxypyridin-2-yl)acetate

To a stirred solution of 2-iodo-5-isopropoxypyridine (1 g, 3.80 mmol) indimethyl sulfoxide (10 mL) was added ethyl 2-bromo-2,2-difluoroacetate(1 mL, 7.60 mmol), copper (0.6 g, 10.09 mmol) and stirred for 16 h at50° C. The reaction mixture was neutralized with aqueous saturatedammonium chloride solution and extracted with ethyl acetate (3×40 mL).The combined organic layers were washed with water (2×20 mL), brine (20mL), dried over sodium sulphate and concentrated to afford ethyl2,2-difluoro-2-(5-isopropoxypyridin-2-yl)acetate (500 mg, 2.30 mmol,60%) as a brown liquid. MS (m/z) 259.1.

D. 2,2-Difluoro-2-(5-isopropoxypyridin-2-yl)acetic acid

To a cold (0° C.) stirred solution of2,2-difluoro-2-(5-isopropoxypyridin-2-yl)acetate (500 mg, 2.32 mmol) inmethanol/tetrahydrofuran/water mixture (9 mL, 1:1:1) was added lithiumhydroxide monohydrate (280 mg, 6.91 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous potassium bisulphate (10 mL)and extracted with ethyl acetate (2×30 mL). The combined organic layerswere washed with brine (10 mL), dried over sodium sulphate, concentratedto afford 2,2-difluoro-2-(5-isopropoxypyridin-2-yl)acetic acid (350 mg,1.51 mmol, 79% yield) as a brown semi solid. MS (ESI) m/z 232.24

E.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-isopropoxypyridin-2-yl)acetamide

To a cold (0° C.) stirred solution of3-(6-((methylamino)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (400 mg, 1.29 mmol) and2,2-difluoro-2-(5-isopropoxypyridin-2-yl)acetic acid (300 mg, 1.29 mmol)in N,N-dimethylformamide (20 mL) was added N,N-diisopropylethylamine(0.7 mL, 3.86 mmol) followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (735 mg, 1.93 mmol) and stirred at roomtemperature for 16 h. The reaction mixture was diluted with water (70mL) and extracted with ethyl acetate (2×40 mL). The combined organiclayers were washed with brine (30 mL), dried over sodium sulphate andconcentrated. The resultant residue was purified by Reveleris C-18reversed phase column using 58% acetonitrile in aqueous formic acid(0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-isopropoxypyridin-2-yl)acetamide (70 mg, 0.14 mmol, 11% yield) as an off whitesolid. MS (ESI) m/z 487.20 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s,1H), 9.55 (br t, J=6.1 Hz, 1H), 8.36 (d, J=2.6 Hz, 1H), 7.76-7.66 (m,2H), 7.60-7.50 (m, 2H), 7.45 (d, J=8.1 Hz, 1H), 5.11 (dd, J=4.8, 13.2Hz, 1H), 4.80-4.75 (m, 1H), 4.65-4.26 (m, 4H), 3.02-2.83 (m, 1H),2.75-2.54 (m, 1H), 2.46-2.305 (m, 1H), 2.06-1.94 (m, 1H), 1.31 (m, 6H).

Example 1072-(5-Bromopyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. Ethyl 2-(5-bromopyridin-2-yl)-2,2-difluoroacetate

To a stirred solution of 5-bromo-2-iodopyridine (3 g, 10.56 mmol) indimethylsulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate(3.13 g, 15.84 mmol) followed by copper powder (1.74 g, 27.46 mmol) atroom temperature and stirred at 55° C. for 6 h. The reaction mixture wasbasified with aqueous saturated sodium bicarbonate solution andextracted with ethyl acetate (3×20 mL). The combined organic layers werewashed with water (20 mL), brine (20 mL), dried over sodium sulfate andconcentrated. The obtained crude was purified by silica gel columnchromatography (20% ethyl acetate in pet ether) to afford ethyl2-(5-bromopyridin-2-yl)-2,2-difluoroacetate (1.5 g, 5.35 mmol, 60%) as acolorless liquid. MS (ESI) m/z 280.2 [M+1]⁺.

B. 2-(5-Bromopyridin-2-yl)-2,2-difluoroacetic acid

To a stirred solution of ethyl2-(5-bromopyridin-2-yl)-2,2-difluoroacetate (1.5 g, 5.37 mmol) inmixture of tetrahydrofuran:methanol:water (15 mL, 1:1:1) was addedlithium hydroxide monohydrate (677 mg, 16.13 mmol) and stirred at roomtemperature for 4 h. The volatiles were removed under reduced pressureand the resultant crude product was dissolved in water (15 mL), washedwith ethyl acetate (2×10 mL). Aqueous layer was acidified with 1Nhydrochloride aqueous solution and extracted with ethyl acetate (3×15mL). The combined organic layers were washed with brine (15 mL), driedover sodium sulfate and concentrated to afford2-(5-bromopyridin-2-yl)-2,2-difluoroacetic acid (900 mg, 3.57 mmol, 69%yield) as semi-solid compound. MS (ESI) m/z 252.2 [M+H]⁺.

C.2-(5-Bromopyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a cold solution of 2-(5-bromopyridin-2-yl)-2,2-difluoroacetic acid(243 mg, 0.97 mmol) in pyridine (6 mL) was added phosphorus oxychloride(1.8 mL, 2.9 mmol) in drop wise and stirred at 0-5° C. for 1 h. Then,3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) was added and stirred at roomtemperature for 2 h. The reaction mixture was basified with saturatedsodium bicarbonate solution and extracted with ethyl acetate (3×15 mL).The combined organic layers were washed with water (15 mL), brine (15mL), dried over sodium sulfate, filtered and concentrated. The resultantresidue was purified by Reveleris C-18 reversed phase columnchromatography (50-55% acetonitrile in 0.1% aqueous formic acid (toafford2-(5-bromopyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(33 mg, 0.065 mmol, 7% yield) as white solid. MS (ESI) m/z 507.8 [M+1]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.68 (t, J=4.5 Hz, 1H), 8.89(d, J=1.6 Hz, 1H), 8.31 (dd, J=8.4, 2.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H),7.72 (d, J=8.0 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 5.11 (dd,J=13.2, 5.2 Hz, 1H), 4.50 (d, J=6.4 Hz, 2H), 4.46 (d, J=17.9 Hz, 1H),4.32 (d, J=17.6 Hz, 1H), 2.95-2.87 (m, 1H), 2.66-2.55 (m, 1H), 2.45-2.30(m, 1H), 2.05-1.96 (m, 1H).

Example 108N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-(trifluoromethoxy)phenyl)acetamide

A. (2-Fluoro-6-(trifluoromethoxy)phenyl)trimethylsilane

To a cold (−78° C.) stirred solution of1-fluoro-3-(trifluoromethoxy)benzene (2.0 g, 11.11 mmol) and TMEDA (1.3mL, 11.11 mmol) in dry tetrahydrofuran (20 mL) was added sec-butyllithium (1.4M in cyclohexane, 8 mL) and stirred for 2 h. To thisreaction mixture was added trimethylsilyl chloride (1.81 g, 16.66 mmol)at −78° C. and stirred for 1 h at room temperature. The reaction mixturewas quenched with aqueous ammonium chloride solution and extracted withdiethylether (2×50 mL). The combined organic layers were washed withwater (50 mL), brine (50 mL), dried over sodium sulfate and concentratedto afford (2-fluoro-6-(trifluoromethoxy)phenyl)trimethylsilane (1.8 g,7.14 mmol, 64% yield). ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.35 (dt, J=6.6,8.2 Hz, 1H), 7.05-7.00 (m, 1H), 6.92 (t, J=8.3 Hz, 1H), 0.41-0.33 (m,9H).

B. (6-Fluoro-3-iodo-2-(trifluoromethoxy)phenyl)trimethylsilane

To a cold (−78° C.) stirred solution of 2,2,6,6-tetramethylpiperidine(897 mg, 6.34 mmol) in dry tetrahydrofuran (20 mL) was added n-butyllithium (2.5M in n-hexane, 2.5 mL, 6.34 mmol) slowly, followed by(2-fluoro-6-(trifluoromethoxy)phenyl)trimethylsilane (1.6 g, 6.34 mmol)in tetrahydrofuran (5 mL) and stirred for 2 h at same temperature.Iodine (2.4 g, 9.52 mmol) in dry tetrahydrofuran (10 mL) was added tothis reaction mixture at −78° C. and allowed to stir at 0° C. for 1 h.The reaction mixture was quenched with aqueous ammonium chloridesolution and extracted with diethyl ether (2×50 mL). The combinedorganic layers were washed with water (50 mL), brine (50 mL), dried oversodium sulfate and concentrated to afford(6-fluoro-3-iodo-2-(trifluoromethoxy)phenyl)trimethylsilane (2.0 g, 5.29mmol, 84% yield). GCMS (m/z) 378.1.

C. Ethyl 2,2-difluoro-2-(4-fluoro-2-(trifluoromethoxy)phenyl)acetate

To a stirred solution of(6-fluoro-3-iodo-2-(trifluoromethoxy)phenyl)trimethylsilane (2.0 g, 5.29mmol) in dimethyl sulfoxide (30 mL) in sealed tube was added ethyl2-bromo-2,2-difluoroacetate (2.1 g, 10.58 mmol) followed by copper (874mg, 13.76 mmol) and stirred at 55° C. for 16 h. The reaction mixture wasquenched with aqueous ammonium chloride solution and extracted withethyl acetate (3×100 mL). The combined organic layers were washed withwater (100 mL), brine (50 mL), dried over sodium sulfate, filtered andconcentrated to afford ethyl2,2-difluoro-2-(4-fluoro-2-(trifluoromethoxy)phenyl)acetate (1.5 g, 4.96mmol, 94% yield). GCMS (m/z) 302.1.

D. 2,2-Difluoro-2-(4-fluoro-2-(trifluoromethoxy)phenyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(4-fluoro-2-(trifluoromethoxy)phenyl)acetate (1.5 g, 4.96mmol) in methanol:tetrahydrofuran:water mixture (15 mL, 1:1:1) was addedlithium hydroxide monohydrate (1.4 g, 14.90 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was diluted with water (50mL), acidified with aqueous potassium bisulfate solution and extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith brine (50 mL), dried over sodium sulfate, filtered was concentratedto afford 2,2-difluoro-2-(4-fluoro-2-(trifluoromethoxy)phenyl)aceticacid (1.0 g, 3.64 mmol, 73% yield). LCMS (ESI) m/z 273.26 [M−1]⁻.

E.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-(trifluoromethoxy)phenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(4-fluoro-2-(trifluoromethoxy)phenyl)acetic acid (300 mg,1.09 mmol) in pyridine (5 mL) was added phosphoryl chloride (0.3 mL,3.28 mmol) dropwise and stirred at 0-5° C. for 1 h.3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (338 mg, 1.09 mmol) was added to this reaction mixture andstirred at room temperature for 1 h. The reaction mixture wasneutralized with aqueous saturated sodium bicarbonate (up to pH-8) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×30 mL), brine (30 mL) and dried over sodiumsulphate and was concentrated to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-(trifluoromethoxy)phenyl)acetamide(37 mg, 0.06 mmol, 6% yield) as an off white solid. LCMS (ESI) m/z530.07 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ (ppm) 10.98 (s, 1H), 9.78 (brt, J=5.9 Hz, 1H), 7.82 (t, J=8.6 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.63(br d, J=11.4 Hz, 1H), 7.51-7.38 (m, 3H), 5.11 (br dd, J=5.1, 13.2 Hz,1H), 4.56-4.40 (m, 3H), 4.31 (d, J=17.6 Hz, 1H), 3.00-2.83 (m, 1H),2.66-2.54 (m, 1H), 2.44-2.30 (m, 1H), 2.08-1.93 (m, 1H).

Example 109N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluorocyclohexyl)acetamide

A. 8-Fluoro-1,4-dioxaspiro[4.5]dec-7-ene

To a stirred solution of 1,4-dioxaspiro[4.5]decan-8-one (12 g, 76.92mmol) in pyridine (120 mL) was added diethylamino sulfur trifluoride (37g, 230 mmol) at 0° C. and stirred at room temperature for 48 h. Thereaction mixture was quenched with aqueous sodium bicarbonate solutionand extracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with brine (100 mL), dried over sodium sulfate, filtered andconcentrated. Obtained crude was purified by column chromatography(100-200 silica gel, 10% ethyl acetate in pet ether) to afford8-fluoro-1,4-dioxaspiro[4.5]dec-7-ene (6.5 g, 41 mmol, 54% yield) as acolourless liquid. MS (ESI) m/z 158.1 [M]⁺.

B. 8-Fluoro-1,4-dioxaspiro[4.5]decane

To a stirred solution of 8-fluoro-1,4-dioxaspiro[4.5]dec-7-ene (1 g,3.53 mmol) in ethyl acetate (15 mL) was added a slurry of 10% palladiumon charcoal (200 mg) in ethyl acetate under nitrogen stream. Thereaction mixture was stirred at room temperature for 4 h under hydrogenatmosphere. The hydrogen atmosphere was evacuated and the reactionmixture was filtered through a Celite pad, filtrate was concentrated toafford to afford 8-fluoro-1,4-dioxaspiro[4.5]decane (500 mg, 1.3 mmol,37% yield) as a colorless liquid. MS (ESI) m/z 160.1 [M]⁺.

C. 4-Fluorocyclohexanone

To a stirred solution of 8-fluoro-1,4-dioxaspiro[4.5]decane (3.5 g,21.87 mmol) in tetrahydrofuran (20 mL) was added 20 mL of 4N aqueoushydrochloric acid at 0° C. and stirred at room temperature for 6 h. Thereaction mixture was diluted with water (10 mL) and basified withaqueous sodium bicarbonate solution and extracted with ethyl acetate(3×30 mL). The combined organic layers were washed with water (30 mL),brine (30 mL), dried over sodium sulfate and concentrated to afford4-fluorocyclohexanone (1.2 g, 10.34 mmol, 48% yield) as a colorlessliquid. MS (ESI) m/z 116.1 [M]⁺

D. Ethyl 2,2-difluoro-2-(4-fluoro-1-hydroxycyclohexyl)acetate

To a stirred solution of 4-fluorocyclohexanone (1.6 g, 13.7 mmol) intetrahydrofuran (20 mL) was added cerium(III) chloride heptahydrate (340mg 1.37 mmol) followed by zinc (1.07 g, 16.55 mmol) and ethyl2-bromo-2,2-difluoroacetate (3.35 g, 16.55 mmol) at 0° C. and stirred atroom temperature for 16 h. The reaction mixture was diluted with water(20 mL) and extracted with ethyl acetate (3×20 mL). The combined organiclayers were washed with brine (20 mL), dried over sodium sulfate,filtered and concentrated. The obtained crude product was purified byflash chromatography (30% ethyl acetate in pet ether) to afford ethyl2,2-difluoro-2-(4-fluoro-1-hydroxycyclohexyl)acetate (1.1 g, 4.58 mmol,34% yield) as a colorless liquid. ¹H NMR (300 MHz, DMSO-d₆) δ 5.60 (s,1H), 4.83 (dt, J=49.2, 2.7 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 1.82-1.64(m, 8H), 1.26 (t, J=7.0 Hz, 3H).

E. Ethyl 2,2-difluoro-2-(4-fluorocyclohex-1-enyl)acetate

To a stirred solution of ethyl2,2-difluoro-2-(4-fluoro-1-hydroxycyclohexyl)acetate (0.75 g, 3.12 mmol)in pyridine (22.6 mL) was added thionyl chloride (3.72 g, 31.25 mmol) at0° C. and stirred at room temperature for 16 h. The reaction mixture wasdiluted with water (10 mL), basified with aqueous sodium bicarbonatesolution and extracted with ethyl acetate (3×15 mL). The combinedorganic layers were washed with water (15 mL), brine (15 mL), dried oversodium sulfate, filtered and concentrated. The obtained crude waspurified by silica gel column chromatography (5% ethyl acetate in petether) to afford ethyl 2,2-difluoro-2-(4-fluorocyclohex-1-enyl)acetate(0.3 g, 1.35 mmol, 43% yield) as a colorless liquid. MS (ESI) m/z 221.9[M]⁺.

F. Ethyl 2,2-difluoro-2-(4-fluorocyclohexyl)acetate

To a stirred solution of ethyl2,2-difluoro-2-(4-fluorocyclohex-1-enyl)acetate (200 mg, 0.9 mmol) inethyl acetate (10 mL) was added a slurry of 10% platinum oxide (20 mg)in ethyl acetate under nitrogen stream. The reaction mixture was stirredunder 60 psi hydrogen pressure at room temperature for 16 h. Thehydrogen atmosphere was evacuated and reaction mixture was filteredthrough a Celite pad, filtrated and concentrated to afford ethyl2,2-difluoro-2-(4-fluorocyclohexyl)acetate (100 mg, 0.44 mmol, 50%yield) as a colourless liquid. ¹H NMR (300 MHz, CDCl₃) δ 4.83 (dt,J=49.2, 2.7 Hz, 1H), 4.34 (q, J=7.2 Hz, 2H), 2.16-1.98 (m, 4H),1.70-1.57 (m, 4H), 1.51-1.41 (m, 1H), 1.26 (t, J=6.6 Hz, 3H).

G. 2,2-Difluoro-2-(4-fluorocyclohexyl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(4-fluorocyclohexyl)acetate (100 mg, 0.446 mmol) inmixture of tetrahydrofuran:methanol:water (6 mL, 1:1:1) was addedlithium hydroxide monohydrate (56 mg, 1.34 mmol) and stirred at roomtemperature for 4 h. The volatiles were removed under reduced pressureand the obtained crude was dissolved in water (5 mL), washed with ethylacetate (2×5 mL). Aqueous layer was acidified with 1N hydrochlorideaqueous solution and extracted with ethyl acetate (3×5 mL). The combinedorganic layers were washed with brine (5 mL), dried over sodium sulfate,filtered and concentrated to afford2,2-difluoro-2-(4-fluorocyclohexyl)acetic acid (50 mg, 0.255 mmol, 59%yield) as semi-solid compound. ¹H NMR (300 MHz, CDCl₃) δ 4.82 (dt,J=42.2, 6.6 Hz, 1H), 2.18-1.20 (m, 10H).

H.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluorocyclohexyl)acetamide

To an ice cold solution of 2,2-difluoro-2-(4-fluorocyclohexyl)aceticacid (190 mg, 0.97 mmol) in pyridine (9 mL) was added phosphorusoxychloride (445 mg, 2.91 mmol) drop wise and stirred at 0-5° C. for 1h. Then, 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride was added into the reaction mixture and stirred at roomtemperature for 2 h. The reaction mixture was basified with aqueoussaturated sodium bicarbonate and extracted with ethyl acetate (3×15 mL).The combined organic layers were washed with brine (15 mL), dried oversodium sulfate, filtered and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase column chromatography (50-55%acetonitrile in 0.1% aqueous formic acid) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluorocyclohexyl)acetamide(33 mg, 0.073 mmol, 7% yield) as white solid. MS (ESI) m/z 452.15[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.56 (t, J=5.6 Hz,1H), 7.70 (d, J=8.1 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J=8.1 Hz, 1H), 5.11(dd, J=13.2, 5.4 Hz, 1H), 4.84 (d, J=48.6 Hz, 1H), 4.45 (d, J=17.1 Hz,1H), 4.44 (d, J=6.3 Hz, 2H), 4.31 (d, J=17.4 Hz, 1H), 2.96-2.72 (m, 1H),2.62-2.51 (m, 1H), 2.40-2.21 (m, 2H), 2.07-1.90 (m, 4H), 1.62-1.41 (m,6H).

Example 110N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(methylsulfonyl)phenyl)acetamide

A. 1-Iodo-4-(methylsulfonyl)benzene

To a stirred solution of 1-bromo-4-(methylsulfonyl)benzene (2 g, 8.506mmol) in 1,4-dioxane (15 mL) was added sodium iodide (2.55 g, 17.01mmol), copper iodide (80 mg, 0.42 mmol),trans-N,N′-dimethylcyclohexane-1,2-diamine (133 mg, 0.93 mmol) at roomtemperature and stirred at 110° C. for 16 h in sealtube. The reactionmixture was quenched with water (50 mL) and extracted with ethyl acetate(3×200 mL). The combined organic layers were washed with water (2×50mL), brine (50 mL), dried over sodium sulphate and concentrated toafford 1-iodo-3-(methylsulfonyl)benzene (1.8 g, 6.38 mmol, 75% yield) asa brown solid. LCMS (ESI) m/z 283.16 [M+H]⁺.

B. Ethyl 2,2-difluoro-2-(4-(methylsulfonyl)phenyl)acetate

To a stirred solution of 1-iodo-4-(methylsulfonyl)benzene (500 mg, 1.77mmol) in dimethyl sulfoxide (5 mL) was added ethyl2-iodo-2,2-difluoroacetate (0.32 mL, 2.313 mmol), copper (107 mg, 1.68mmol) and stirred for 16 h at room temperature. The reaction mixture wasneutralized with aqueous saturated ammonium chloride solution andextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with water (2×50 mL), brine (50 mL), dried over sodiumsulphate and concentrated. The resultant residue was purified bysilica-gel (100-200 mesh, 20% ethyl acetate in hexanes) to afford toafford ethyl 2,2-difluoro-2-(4-(methylsulfonyl)phenyl)acetate (250 mg,0.899 mmol, 50%) as an off-white solid. MS (ESI) m/z 279.26 [M+1]⁺.

C. 2,2-Difluoro-2-(4-(methylsulfonyl)phenyl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(4-(methylsulfonyl)phenyl)acetate (250 mg, 0.899 mmol) inin methanol/tetrahydrofuran/water (6 mL, 1:1:1) was added lithiumhydroxide monohydrate (75 mg, 0.798 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous potassium bisulphate (10 mL)and extracted with ethyl acetate (3×50 mL). The combined organic layerswere washed with brine (50 mL), dried over sodium sulphate andconcentrated to afford 2,2-difluoro-2-(4-(methylsulfonyl)phenyl)aceticacid (180 mg, 0.72 mmol, 80% yield) as a gummy solid. MS (ESI) m/z249.26 [M−1]⁺.

D.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(methylsulfonyl)phenyl)acetamide

To a cold (0° C.) stirred solution of 22,2-difluoro-2-(4-(methylsulfonyl)phenyl)acetic acid (194 mg, 0.776mmol) in pyridine (10 mL) was added phosphoryl chloride (0.18 mL, 1.94mmol) drop wise and stirred at 0-5° C. for 30 min. To this,3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (200 mg, 0.64 mmol) was added and stirred at roomtemperature for 2 h. The reaction mixture was neutralized with aqueoussaturated sodium bicarbonate (up to pH-8) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with water(2×50 mL), brine (50 mL), dried over sodium sulphate and concentrated.The resultant residue was purified by grace column chromatography using52% ACN in 0.1% aqueous formic acid solution as a eluent to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(methylsulfonyl)phenyl)acetamide(70 mg, 0.138 mmol, 21% yield) as an off-white solid. MS (ESI) m/z506.06 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.78 (br t,J=6.1 Hz, 1H), 8.11 (d, J=8.3 Hz, 2H), 7.88 (d, J=8.3 Hz, 2H), 7.69 (d,J=7.8 Hz, 1H), 7.42-7.34 (m, 2H), 5.10 (dd, J=4.9, 13.2 Hz, 1H),4.53-4.37 (m, 3H), 4.28 (d, J=17.2 Hz, 1H), 3.29 (s, 3H), 2.98-2.87 (m,1H), 2.68-2.55 (m, 1H), 2.46-2.31 (m, 1H), 2.06-1.94 (m, 1H).

Example 111N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(methylsulfonyl)phenyl)acetamide

A. 1-Iodo-3-(methylsulfonyl)benzene

To a stirred solution of 1-bromo-3-(methylsulfonyl)benzene (1 g, 4.25mmol) in 1,4-dioxane (15 mL) was added sodium iodide (1.92 g, 12.76mmol), copper iodide (81 mg, 0.425 mmol),trans-N,N′-dimethylcyclohexane-1,2-diamine (90 mg, 0.63 mmol) at roomtemperature and stirred at 110° C. for 16 h in sealtube. The reactionmixture was quenched with water (50 mL) and extracted with ethyl acetate(3×200 mL). The combined organic layers were washed with water (2×50mL), brine (50 mL), dried over sodium sulphate and concentrated toafford 1-iodo-3-(methylsulfonyl)benzene (900 g, 3.19 mmol, 75% yield) asa brown solid. LCMS (ESI) m/z 282.85 [M+H]⁺.

B. Ethyl 2,2-difluoro-2-(3-(methylsulfonyl)phenyl)acetate

To a stirred solution of 1-Iodo-3-(methylsulfonyl)benzene (900 mg, 3.19mmol) in dimethylsulfoxide (15 mL) was added ethyl2-iodo-2,2-difluoroacetate (0.56 mL, 4.147 mmol), copper (527 mg, 8.29mmol) and stirred for 16 h at room temperature. The reaction mixture wasneutralized with aqueous saturated ammonium chloride solution andextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with water (2×50 mL), brine (50 mL), dried over sodiumsulphate and concentrated. The resultant residue was purified bysilica-gel (100-200 mesh, 12% ethyl acetate in hexane) to afford ethyl2,2-difluoro-2-(3-(methylsulfonyl)phenyl)acetate (850 mg, 3.05 mmol,95%) as an off-white solid. MS (ESI) m/z 320.32 [M+1]⁺ (ACN (+41)adduct)

C. 2,2-Difluoro-2-(3-(methylsulfonyl)phenyl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(3-(methylsulfonyl)phenyl)acetate (800 mg, 2.87 mmol) inin methanol/tetrahydrofuran/water (10 mL, 1:1:1) was added lithiumhydroxide monohydrate (361 mg, 8.61 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous potassium bisulphate (20 mL)and extracted with ethyl acetate (3×50 mL). The combined organic layerswere washed with brine (50 mL), dried over sodium sulphate andconcentrated to afford 2,2-difluoro-2-(3-(methylsulfonyl)phenyl)aceticacid (650 mg, 1.74 mmol, 70% yield) as an gummy solid. MS (ESI) m/z251.07 [M+1]⁺.

D.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(methylsulfonyl)phenyl)acetamide

To a cold (0° C.) stirred solution of 22,2-difluoro-2-(3-(methylsulfonyl)phenyl)acetic acid (291 mg, 1.16 mmol)in pyridine (10 mL) was added phosphoryl chloride (0.27 mL, 2.91 mmol)dropwise and stirred at 0-5° C. for 30 min. To this reaction mixture wasthen added 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) and stirred at room temperature for 2h. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate (up to pH-8) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (2×50 mL), brine (50 mL),dried over sodium sulphate and concentrated. The resultant residue waspurified by grace column chromatography using 52% of ACN-0.1% formicacid in water as a eluent to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(methylsulfonyl)phenyl)acetamide(72 mg, 0.142 mmol, 15% yield) as an off-white solid. MS (ESI) m/z506.01 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.98 (s, 1H) 9.80 (br t,J=5.85 Hz, 1H), 8.12-8.09 (m, 2H), 7.96 (d, J=8.4 Hz, 1H), 7.90-7.80 (m,1H), 7.67 (d, J=7.68 Hz, 1H), 7.41 (s, 1H), 7.36 (d, J=7.8 Hz, 1H), 5.10(dd, J=13.16, 5.12 Hz, 1H), 4.54-4.20 (m, 4H), 3.30 (d, J=8.04 Hz, 3H),3.01-2.79 (m, 1H), 2.67-2.55 (m, 1H), 2.47-2.30 (m, 1H), 2.06-1.92 (m,1H).

Example 1122-(2-Aminopyrimidin-5-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. Ethyl 2-(2-aminopyrimidin-5-yl)-2,2-difluoroacetate

To a stirred solution of 5-iodopyrimidin-2-amine (1 g, 4.52 mmol) indimethylsulfoxide (20 mL) was reacted with ethyl2-bromo-2,2-difluoroacetate (1.1 mL, 9.04 mmol), copper (0.75 g, 11.76mmol) and stirred for 16 h at 50° C. The reaction mixture wasneutralized with aqueous saturated ammonium chloride solution andextracted with ethyl acetate (3×50 mL). The combined organic layer waswashed with water (2×10 mL), brine (10 mL) and dried over sodiumsulphate and was concentrated to give ethyl2-(2-aminopyrimidin-5-yl)-2,2-difluoroacetate (600 mg, 2.76 mmol, 61%)as a brown liquid. GCMS (m/z) 217.1.

B. 2-(2-Aminopyrimidin-5-yl)-2,2-difluoroacetic acid

To a cold (0° C.) stirred solution of ethyl2-(2-aminopyrimidin-5-yl)-2,2-difluoroacetate (500 mg, 2.30 mmol) in inethanol/tetrahydrofuran/water (12 mL, 1:1:1) was added lithium hydroxidemonohydrate (290 mg, 6.91 mmol) and stirred at room temperature for 2 h.The reaction mixture was concentrated and the residue was neutralizedwith 10% aqueous potassium bisulphate (10 mL) and extracted with ethylacetate (2×30 mL). The combined organic layer was washed with brine (10mL), dried over sodium sulphate and concentrated to afford2-(2-aminopyrimidin-5-yl)-2,2-difluoroacetic acid (300 mg, 1.58 mmol,69% yield) as a brown semi solid. MS (ESI) m/z 190.22. [M+1]⁺.

C.2-(2-Aminopyrimidin-5-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a cold (0° C.) stirred solution of2-(2-aminopyrimidin-5-yl)-2,2-difluoroacetic acid (800 mg, 4.23 mmol)and 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (915 mg, 2.96 mmol) in N,N-dimethylformamide (30 mL) wasadded N,N-diisopropylethylamine (2.3 mL, 12.69 mmol) followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (2.4 g, 6.34 mmol) and stirring at roomtemperature for 16 h. The reaction mixture was diluted with water (70mL) and extracted with ethyl acetate (2×20 mL) and the combined organiclayer was washed with brine (30 mL), dried over sodium sulphate andconcentrated dried under vacuum. The product was purified by RevelerisC-18 reversed phase column using 40% acetonitrile in aqueous formic acid(0.1%) to afford2-(2-aminopyrimidin-5-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(45 mg, 1.01 mmol, 15% yield) as an off-white solid. MS (ESI) m/z 445.44[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.96 (s, 1H), 9.59 (br t, J=5.8 Hz,1H), 8.36 (s, 2H), 7.67 (d, J=7.7 Hz, 1H), 7.43 (s, 1H), 7.37 (d, J=8.0Hz, 1H), 7.26 (s, 2H), 5.10 (dd, J=5.2, 13.4 Hz, 1H), 4.65-4.24 (m, 4H),3.02-2.83 (m, 1H), 2.67-2.54 (m, 1H), 2.46-2.30 (m, 1H), 2.01-1.95 (m,1H).

Example 113N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-(trifluoromethylthio)pyridin-2-yl)acetamide

A. tert-Butyl 6-bromopyridin-3-ylcarbamate

To a stirred solution of 6-bromopyridin-3-amine (7 g, 40.46 mmol) indichloromethane (70 mL) was added di-tert-butyl dicarbonate (10.58 mL,48.55 mmol) followed by 4-dimethylaminopyridine (0.99 g, 8.09 mmol),triethyl amine (0.99 g, 8.09 mmol) at 0° C. and stirred at roomtemperature for 6 h. The reaction mixture was diluted with water (50 mL)and extracted with dichloromethane (3×50 mL). The combined organiclayers were washed with brine (50 mL), dried over sodium sulfate,filtered and concentrated. The obtained crude was purified by silica gelcolumn chromatography (5% ethyl acetate/pet-ether) to afford tert-butyl6-bromopyridin-3-ylcarbamate (6 g, 22.05 mmol, 54% yield) as a colorlessliquid. MS (ESI) m/z 273.22 [M+1]⁺.

B. Ethyl2-(5-(tert-butoxycarbonylamino)pyridin-2-yl)-2,2-difluoroacetate

To a stirred solution of tert-butyl 6-bromopyridin-3-ylcarbamate (6 g,16.08 mmol) in dimethyl sulfoxide (40 mL) was added ethyl2-bromo-2,2-difluoroacetate (4.89 mL, 24.12 mmol) followed by copperpowder (2.65 g, 41.73 mmol) at room temperature and stirred at 60° C.for 6 h. The reaction mixture was diluted with water and filteredthrough a Celite pad. Filtrate was extracted with ethyl acetate (3×50mL) and the combined organic layers were washed with brine (50 mL),dried over sodium sulfate, filtered and concentrated. The obtained crudewas purified by silica gel column chromatography (5% ethylacetate/pet-ether) to afford ethyl2-(5-(tert-butoxycarbonylamino)pyridin-2-yl)-2,2-difluoroacetate (4 g,12.65 mmol, 57% yield) as a colorless liquid. ¹H NMR (300 MHz, CDCl₃) δ8.42 (d, J=2.1 Hz, 1H), 8.16 (d, J=6.9 Hz, 1H), 7.66 (d, J=9.0 Hz, 1H),6.67 (b s, 1H), 4.36 (q, J=7.1 Hz, 2H), 1.53 (s, 9H), 1.32 (t, J=7.2 Hz,3H).

C. Ethyl 2,2-difluoro-2-(5-thiocyanatopyridin-2-yl)acetate

A stirred solution of ethyl2-(5-(tert-butoxycarbonylamino)pyridin-2-yl)-2,2-difluoroacetate (4 g,12.65 mmol) in 6N HCl (80 mL) at 0° C. and stirred at room temperaturefor 30 min. Then, sodium nitrite (0.87 g, 12.65 mmol) was added into thereaction mixture followed by copper(I) thiocyanate (0.77 g, 6.32 mmol),potassium thiocyanate (0.99 g, 8.09 mmol) at −5° C. and stirred at roomtemperature for 1 h. The reaction mixture was poured into saturatedaqueous sodium bicarbonate solution and extracted with ethyl acetate(3×40 mL). The combined organic layers were washed with brine (40 mL),dried over sodium sulfate, filtered and concentrated. The obtained crudewas purified by silica gel column chromatography (5% ethylacetate/pet-ether) to afford ethyl2,2-difluoro-2-(5-thiocyanatopyridin-2-yl)acetate (0.7 g, 2.71 mmol, 21%yield) as a colourless liquid. MS (ESI) m/z 259.23 [M+1]⁺.

D. Ethyl 2,2-difluoro-2-(5-(trifluoromethylthio)pyridin-2-yl)acetate

To a stirred solution of ethyl2,2-difluoro-2-(5-thiocyanatopyridin-2-yl)acetate (700 mg, 2.71 mmol) intetrahydrofuran (10 mL) was added trifluoromethyltrimethylsilane (770mg, 5.42 mmol) followed by tetra-n-butylammonium fluoride (1.08 mL, 1.08mmol) at 0° C. and stirred at room temperature for 16 h. The reactionmixture was quenched with aqueous sodium bicarbonate solution andextracted with ethyl acetate (3×10 mL). The combined organic layers werewashed with brine (10 mL), dried over sodium sulfate, filtered andconcentrated. The obtained crude was purified by flash columnchromatography (100-200 silica gel, 2% ethyl acetate/pet-ether) toafford ethyl 2,2-difluoro-2-(5-(trifluoromethylthio)pyridin-2-yl)acetate(170 mg, 0.56 mmol, 21% yield) as a colourless liquid. MS (ESI) m/z302.27 [M+1]⁺.

E. 2,2-Difluoro-2-(5-(trifluoromethylthio)pyridin-2-yl)acetic acid

To a stirred solution of ethyl2,2-difluoro-2-(5-(trifluoromethylthio)pyridin-2-yl)acetate (170 mg,0.56 mmol) in tetrahydrofuran:ethanol:water (5 mL, 1:1:1) was addedlithium hydroxide monohydrate (71 mg, 1.69 mmol) and stirred at roomtemperature for 4 h. The volatiles were removed under reduced pressureand obtained crude was dissolved in water (5 mL) and washed with ethylacetate (2×4 mL). The aqueous layer was acidified with aqueous potassiumbisulphate solution and extracted with ethyl acetate (3×5 mL). Thecombined organic layers were washed with brine (5 mL), dried over sodiumsulfate, filtered and concentrated to afford2,2-difluoro-2-(5-(trifluoromethylthio)pyridin-2-yl)acetic acid (140 mg,0.51 mmol, 91% yield) as a semi-solid compound. MS (ESI) m/z 274.18[M+1]⁺.

F.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-(trifluoromethylthio)pyridin-2-yl)acetamide

To an ice cold solution of2,2-difluoro-2-(5-(trifluoromethylthio)pyridin-2-yl)acetic acid (220 mg,0.81 mmol) in pyridine (5 mL) was added phosphorus oxychloride (371 mg,2.42 mmol) drop wise and stirred at 0-5° C. for 1 h. Then,3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (250 mg, 0.81 mmol) was added into the reaction mixtureand stirred at room temperature for 1 h. The reaction mixture wasneutralized with aqueous saturated sodium bicarbonate and extracted withethyl acetate (3×10 mL). The combined organic layers were washed withbrine (10 mL), dried over sodium sulphate, filtered and concentrated.The resultant residue was purified by Reveleris C-18 reversed phasecolumn chromatography (50-55% acetonitrile/0.1% aqueous formic acid) toaffordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-(trifluoromethylthio)pyridine-2-yl)acetamide (45 mg, 0.08 mmol, 10% yield) as an off-whitesolid. MS (ESI) m/z 529.03 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s,1H), 9.77 (t, J=5.4 Hz, 1H), 9.01 (s, 1H), 8.44 (dd, J=7.8, 0.8 Hz, 1H),7.98 (d, J=8.4 Hz, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.50 (s, 1H), 7.44 (d,J=7.5 Hz, 1H), 5.11 (dd, J=12.9, 5.1 Hz, 1H), 4.51 (d, J=6.3 Hz, 2H),4.46 (d, J=17.9 Hz, 1H), 4.31 (d, J=17.6 Hz, 1H), 2.92-2.88 (m, 1H),2.63-2.57 (m, 1H), 2.41-2.36 (m, 1H), 2.02-2.00 (m, 1H).

Example 114N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(methylamino)ethoxy)phenyl)acetamidehydrochloride

A. Ethyl2-(3-(2-(tert-butoxycarbonyl(methyl)amino)ethoxy)phenyl)-2,2-difluoroacetate

To a stirred solution of ethyl 2,2-difluoro-2-(3-hydroxyphenyl)acetate(2 g, 9.25 mmol) in tetrahydrofuran (20 mL) was added tert-butyl2-hydroxyethyl(methyl)carbamate (2.43 g 13.88 mmol), N,N-diisopropylazodicarboxylate (1.87 g 9.25 mmol) followed by triphenyl phosphine (2.4g, 9.25 mmol) at room temperature and stirred at 50-55° C. for 16 h. Thereaction mass was directly concentrated. The resultant residue waspurified by column chromatography (silica-gel 100-200) 30%ethylacetate—hexanes as a eluent to afford ethyl2-(3-(2-(tert-butoxycarbonyl(methyl)amino)ethoxy)phenyl)-2,2-difluoroacetate (1 g, 4.0 mmol, 29%yield) as brown liquid. MS (ESI) m/z 274.2 [M−100]⁺.

B.2-(3-(2-(tert-Butoxycarbonyl(methyl)amino)ethoxy)phenyl)-2,2-difluoroaceticacid

To a cold (0° C.) stirred solution of ethyl 2-(3-(2-(tert-butoxycarbonyl(methyl)amino)ethoxy)phenyl)-2,2-difluoroacetate (1.0 g, 2.67mmol) in Methanol/Tetrahydrofuran/water (15 mL, 1:1:1) was added lithiumhydroxide monohydrate (224.5 mg, 5.64 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous potassium bisulphate (10 mL)and extracted with ethyl acetate (2×50 mL). The combined organic layerwas washed with brine (20 mL), dried over sodium sulphate andconcentrated to give ethyl 2-(3-(2-(tert-butoxycarbonyl(methyl)amino)ethoxy)phenyl)-2,2-difluoroacetic acid (600 mg, 1.73 mmol,65% yield) as a brown semi solid. MS (ESI) m/z 343.8 [M−1]⁺.

C. tert-Butyl2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methylamino)-1,1-difluoro-2-oxoethyl)phenoxy)ethyl(methyl)carbamate

To a solution of ethyl2-(3-(2-(tert-butoxycarbonyl(methyl)amino)ethoxy)phenyl)-2,2-difluoroaceticacid (447.8 mg, 1.44 mmol) in N,N-dimethylformamide (20 mL) was added(3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (500 mg, 1.44 mmol) was added sub sequentiallydiisopropylethylamine (561.8 mg, 4.34 mmol) and1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (825.9 g, 2.17 mmol) at room temperature andreaction was continued to room for 2 h. The reaction mixture was pouredin ice cold water (40 mL) to observed off-white solid. The resultantresidue was purified by Reveleris C-18 reverse phase columnchromatography using 45-50% acetonitrile in aqueous formic acid (0.1%)to give tert-butyl2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methylamino)-1,1-difluoro-2-oxoethyl)phenoxy)ethyl(methyl)carbamate(200 mg, 0.33 mmol, 20% yield) as an off-white solid. MS (ESI) m/z 501[M−100]⁺ (De Boc mass).

D.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(methylamino)ethoxy)phenyl)acetamidehydrochloride

To tert-butyl2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methylamino)-1,1-difluoro-2-oxoethyl)phenoxy)ethyl(methyl)carbamate(160 mg, 0.26 mmol), 4M hydrochloric acid in dioxane was (5 mL) wasadded and stirred at room temperature for 4 h. The solution wasdistilled off under reduced pressure and washed with diethylether toafford 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (60 mg, 0.11 mmol, 42% yield) as an off white solid. MS(ESI) m/z 501.59 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.99 (s, 1H),9.87-9.58 (m, 1H), 8.98 (br s, 2H), 7.68 (d, J=7.8 Hz, 1H), 7.53-7.46(m, 1H), 7.44-7.40 (m, 1H), 7.39-7.34 (m, 1H), 7.46-7.32 (m, 1H),7.24-7.16 (m, 3H), 5.11 (dd, J=5.1, 13.5 Hz, 1H), 4.48-4.39 (m, 3H),4.33-4.24 (m, 3H), 3.40-3.25 (m, 2H), 2.97-2.85 (m, 1H), 2.67-2.55 (m,4H), 2.39 (dq, J=4.4, 13.2 Hz, 4H), 2.05-1.94 (m, 1H).

Example 115N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)acetamide

A. 1-tert-Butyl 3-ethyl 2-(6-chloropyridazin-3-yl)malonate

1-Tert-butyl ethyl malonate (26.6 mL, 140.54 mmol) was added drop wiseto a suspension of sodium hydride (12.9 g, 324.32 mmol) in dioxane at10° C. The reaction was stirred at 10° C. for 1 h and then allowed towarm to room temperature. 3,6-dichloropyridazine (20 g, 135.13 mmol) wasthen added portion wise to the reaction at 25° C. and refluxed for 2 hr.The reaction mixture was diluted with ice cold water (500 mL) extractedwith ethyl acetate (5×500 mL). The combined organic layers were washedwith brine (50 mL), dried over sodium sulphate and concentrated. Theresultant residue was purified by column chromatography (100-200 silica)using 6% EtoAc:Hexene to afford 1-tert-butyl 3-ethyl2-(6-chloropyridazin-3-yl)malonate (16 g, 53.33 mmol, 39% yield). LCMS(ESI) m/z 301.31 [M+1]⁺.

B. 1-tert-Butyl 3-ethyl 2-(6-chloropyridazin-3-yl)-2-fluoromalonate

To a solution of 1-tert-butyl 3-ethyl 2-(6-chloropyridazin-3-yl)malonate(16 g, 53.33 mmol) in tetrahydrofuran (200 mL) was added sodium hydride(2.31 g, 58.133 mmol) at 0° C. and stirred for 15 min. A cloudy solutionof SelectFluor (20.5 g, 58.13 mmol) in dry N,N-dimethylformamide (40 mL)was added drop wise at 0° C. over a period of 20 min and then thereaction was allowed to stir at room temperature for 2 h. The reactionwas quenched with ammonium chloride (200 mL) and extracted with ethylacetate (5×500 mL). The combined organic layers were washed with brine(50 mL), dried over sodium sulphate and concentrated. The resultantresidue was purified by column chromatography (100-200 silica) using 5%EtoAc:Hexene to afford 1-tert-butyl 3-ethyl2-(6-chloropyridazin-3-yl)-2-fluoromalonate (11 g, 34.59 mmol, 64%yield). LCMS (ESI) m/z 219.27 [M+1]⁺.

C. Ethyl 2-(6-chloropyridazin-3-yl)-2-fluoroacetate

A solution of 1-tert-butyl 3-ethyl2-(6-chloropyridazin-3-yl)-2-fluoromalonate (11 g, 34.54 mmol) intrifluoroacetic acid:dichloromethane mixture (1:1, 60 mL) was stirred at25° C. for 2 h and then concentrated to dryness over rotary evaporator.The resulting residue was dissolved in ethyl acetate (100 mL), washedwith saturated aqueous sodium bicarbonate solution, dried over sodiumsulphate and then concentrated to dryness to afford ethyl2-(6-chloropyridazin-3-yl)-2-fluoroacetate (6 g, 27.52 mmol 79% yield),LCMS (ESI) m/z 219.06 [M+1]⁺. The material was taken to the next stepwithout further purification.

D. Ethyl 2-fluoro-2-(6-hydroxypyridazin-3-yl)acetate

To a stirred solution of ethyl2-(6-chloropyridazin-3-yl)-2-fluoroacetate (6 g, 27.52 mmol) in aceticacid (20 mL) was added sodium acetate (22.56 g, 275.52 mmol) and stirredfor 16 h at 100° C. The reaction mixture was diluted with ice cold water(500 mL) extracted with ethyl acetate (5×500 mL). The combined organiclayers were washed with brine (50 mL), dried over sodium sulphate andconcentrated. The resultant residue was purified by columnchromatography (100-200 silica) using 30% ethyl acetate in hexanes toafford ethyl 2-fluoro-2-(6-hydroxypyridazin-3-yl)acetate (4 g, 20.00mmol, 72% yield). LCMS (ESI) m/z 201.22 [M+1]⁺.

E. Ethyl 2-fluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)acetate

To a stirred solution of ethyl2-fluoro-2-(6-hydroxypyridazin-3-yl)acetate (4 g, 20.00 mmol) inN,N-dimethylformamide (20 mL) was added methyl iodide (1.86 mL, 30.00mmol), potassium carbonate (8.28 g, 60.00 mmol) at room temperature andstirred for 3 h. The reaction mixture was diluted with water (50 mL) andextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with brine (50 mL), dried over sodium sulphate andconcentrated. The resultant residue was purified by columnchromatography (100-200 silica) using 40% ethyl acetate in hexanes toafford ethyl2-fluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)acetate (3 g, 14.01mmol, 70% yield). LCMS (ESI) m/z 215.66 [M+1]⁺.

F. Ethyl2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)acetate

To a solution of ethyl2-fluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)acetate (3 g 14.01mmol) in dry tetrahydrofuran (30 mL) was added lithiumhexamethyldisilazide (14 mL, 16.82 mmol) drop wise at −78° C. andstirred for 15 minutes. To this, a suspension of SelectFluor (5.9 g,16.8 mmol) in dry N,N-dimethylformamide (10 mL) was added drop wise overa period of 10 min. Upon completion addition, the reaction was allowedto warm to room temperature over a period of 30 min. The reaction wasquenched with saturated ammonium chloride (50 mL) and the organicfractions were distilled off. The residue obtained was diluted with icecold water (500 mL) and extracted with ethyl acetate (5×500 mL). Thecombined organic layers were washed with brine (50 mL), dried oversodium sulphate and concentrated. The resultant residue was purified byCombi-Flash column chromatography (100-200 silica) using 42% ethylacetate in hexanes to afford ethyl2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)acetate (1.2 g,5.17 mmol, 36% yield). LCMS (ESI) m/z 233.33 [M+1]⁺.

G. 2,2-Difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)acetate (1.2 g,5.17 mmol) in tetrahydrofuran:Methanol:water mixture (30 mL, 1:1:1) wasadded lithium hydroxide monohydrate (1.08 g, 25.86 mmol) and stirred atroom temperature for 6 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous hydrochloric acid and extractedwith ethyl acetate (2×50 mL). The combined organic layers were washedwith brine (20 mL), dried over sodium sulphate and concentrated toafford 2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)aceticacid (700 mg, 3.43 mmol, 66% yield) as an off white solid. LCMS (ESI)m/z 205.31[M+1]⁺.

H.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)acetic acid(197.6 mg, 0.968 mmol) in pyridine was added phosphoryl chloride (0.27mL, 2.906 mmol) dropwise and stirred at 0-5° C. for 1 h. To thisreaction mixture was added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.968 mmol) and continued stirring at roomtemperature for 30 min. The reaction mixture was neutralized withaqueous saturated sodium bicarbonate (up to pH-8) and extracted withethyl acetate (3×50 mL). The combined organic layers were washed withwater (2×10 mL), brine (10 mL), dried over sodium sulphate andconcentrated. The resultant residue was purified by Reveleris C-18reversed phase column chromatography using 40-60% acetonitrile inaqueous formic acid (0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)acetamide(70 mg, 0.152 mmol, 15% yield) as an off white solid. MS (ESI) m/z460.52 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ=10.98 (s, 1H), 9.68 (br t,J=5.8 Hz, 1H), 7.79-7.69 (m, 2H), 7.51 (s, 1H), 7.45 (d, J=7.7 Hz, 1H),7.12 (d, J=9.5 Hz, 1H), 5.11 (dd, J=4.9, 13.3 Hz, 1H), 4.58-4.27 (m,4H), 3.66 (s, 3H), 2.99-2.83 (m, 1H), 2.67-2.56 (m, 1H), 2.45-2.29 (m,1H), 2.08-1.93 (m, 1H).

Example 1162-(2-aminopyrimidin-4-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. 4-Iodopyrimidin-2-amine

To an ice cold solution of 4-chloropyrimidin-2-amine (5 g, 38.5 mmol) inhydroiodic acid (100 mL) was added sodium iodide (17.2 g, 115.7 mmol) at0° C. and stirred at room temperature for 2 h. The reaction mixture wasquenched cautiously with aqueous sodium bicarbonate solution at 0° C.and extracted with dichloromethane (3×150 mL). The combined organiclayers were washed water (150 mL), brine (150 mL), dried over sodiumsulphate, filtered and concentrated to afford 4-iodopyrimidine-2-amine(1.55 g, 7.01 mmol, 18% yield) as a colourless liquid. MS (ESI) m/z 222[M+H]⁺.

B. Ethyl 2-(2-aminopyrimidin-4-yl)-2,2-difluoroacetate

To a stirred solution of 4-iodopyrimidine-2-amine (5 g, 22.60 mmol) indimethyl sulfoxide (10 mL) was added ethyl 2-bromo-2,2-difluoroacetate(4.53 mL, 33.92 mmol) followed by copper powder (3.7 g, 58.75 mmol) andstirred at 50° C. for 4 h. The reaction mixture was neutralized withaqueous saturated ammonium chloride solution and extracted with ethylacetate (3×150 mL). The combined organic layers were washed with water(2×50 mL), brine (50 mL), dried over sodium sulphate and concentrated toafford Ethyl 2-(2-aminopyrimidin-4-yl)-2,2-difluoroacetate (1.4 mg, 6.45mmol, 28%) as a brown liquid. MS (ESI) m/z 218 [M+H]⁺.

C. 2-(2-aminopyrimidin-4-yl)-2,2-difluoroacetic acid

To a cold (0° C.) stirred solution of ethyl2-(2-aminopyrimidin-4-yl)-2,2-difluoroacetate (700 mg, 3.22 mmol) intetrahydrofuran was added 1N hydrochloric acid and stirred at roomtemperature for 12 h. The reaction mixture was concentrated and theobtained residue was co-distilled with toluene to afford2-(2-aminopyrimidin-4-yl)-2,2-difluoroacetic acid (550 mg, 2.91 mmol,82% yield) as a white solid. MS (ESI) m/z 188 [M−H]⁺.

D.2-(2-aminopyrimidin-4-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a cold (0° C.) solution of3-(6-((methylamino)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.hydrochloride(683 mg, 2.21 mmol) and 2-(2-aminopyrimidin-4-yl)-2,2-difluoroaceticacid (500 mg, 2.21 mmol) in N,N-dimethylformamide (10 mL) was addedN,N-diisopropylethylamine (1.15 mL, 6.63 mmol) followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (1 g, 2.65 mmol) and stirred at roomtemperature for 16 h. The reaction mixture was diluted with water (70mL) and extracted with ethyl acetate (2×50 mL). The combined organiclayers were washed with brine (30 mL), dried over sodium sulphate andconcentrated. The resultant residue was purified by Reveleris C-18reversed phase column using 58% acetonitrile in aqueous formic acid(0.1%) to afford2-(2-aminopyrimidin-4-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(52 mg, 11.6 mmol, 5% yield) as an off white solid. MS (ESI) m/z 445.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.57 (t, J=6.0 Hz,1H), 8.46 (d, J=4.8 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.60(d, J=7.6 Hz, 1H), 7.07 (s, 1H), 6.86 (d, J=4.8 Hz, 1H), 5.11 (dd,J=13.2, 4.8 Hz, 1H), 4.48 (d, J=5.2 Hz, 2H), 4.46 (d, J=16.9 Hz, 1H),4.31 (d, J=17.2 Hz, 1H), 2.93-2.89 (m, 1H), 2.67-2.58 (m, 1H), 2.40-2.33(m, 1H), 2.01-1.98 (m, 1H).

Example 117N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(pyrimidin-4-yl)acetamide

A. Ethyl 2,2-difluoro-2-(2-(methylthio)pyrimidin-4-yl)acetate

To a stirred solution of 4-chloro-2-(methylthio)pyrimidine (5 g, 21.55mmol) in dimethylsulfoxide (50 mL) was added ethyl2-bromo-2,2-difluoroacetate (8 mL, 62.2 mmol) followed by copper powder(5.93 g, 93.4 mmol) at RT and stirred at 60° C. for 6 h. The reactionmixture was basified with saturated sodium bicarbonate solution andextracted with ethyl acetate (3×20 mL). The combined organic layers werewashed with water (40 mL), brine (40 mL), dried over sodium sulfate,filtered and solvent was concentrated and obtained crude was purified bysilica gel column chromatography using 20% ethyl acetate in pet ether toafford ethyl 2,2-difluoro-2-(3-formylphenyl)acetate (3 g, 12.00 mmol,38%) as a colorless liquid. MS (ESI) m/z 249.66 [M+1]⁺.

B. Ethyl 2,2-difluoro-2-(pyrimidin-4-yl)acetate

Ethyl 2,2-difluoro-2-(2-(methylthio)pyrimidin-4-yl)acetate (2.8 g, 11.29mmol) in tetrahydrofuran was added to trimethylsilane (5.3 mL) at 0° C.and added 10% Pd/C (622 mg) then stirred at room temperature for 5 h.The reaction mixture was filtered through celite pad The combinedorganic layers were washed with brine (10 mL), dried over sodiumsulfate, filtered and concentrated. The obtained crude was purified byflash column chromatography (100-200 silica gel, 10% ethyl acetate inpet ether) to afford ethyl 2,2-difluoro-2-(pyrimidin-4-yl)acetate (800mg, 3.96 mmol, 36% yield) as a colourless liquid MS (ESI) m/z 203.65[M+1]⁺.

C. 2,2-Difluoro-2-(pyrimidin-4-yl)acetic acid

To a stirred solution of ethyl 2,2-difluoro-2-(pyrimidin-4-yl)acetate (1g, 4.95 mmol) in tetrahydrofuran:ethanol:water (15 mL, 1:1:1) was addedlithium hydroxide monohydrate (624 mg, 14.85 mmol) and stirred at roomtemperature for 16 h. The volatiles were removed under reduced pressureand obtained crude was dissolved in water (15 mL) and washed with ethylacetate (2×10 mL). The aqueous layer was acidified with 1N hydrochloridesolution and extracted with ethyl acetate (3×15 mL). The combinedorganic layers were washed with brine (10 mL), dried over sodiumsulfate, filtered and concentrated to2,2-difluoro-2-(pyrimidin-4-yl)acetic acid (800 mg, 4.59 mmol, 92%yield) as semi-solid compound. MS (ESI) m/z 175 [M+1]⁺.

D.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(pyrimidin-4-yl)acetamide

To an ice cold solution of 2,2-difluoro-2-(pyrimidin-4-yl)acetic acid(203 mg, 1.16 mmol) in pyridine (10 mL) was added phosphorus oxychloride(0.27 mL, 2.91 mmol) drop wise and stirred at 0-5° C. for 1 h and thenadded 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.97 mmol) and stirred at room temperature for 30min. The reaction mixture was neutralized with aqueous saturated sodiumbicarbonate and extracted with ethyl acetate (3×15 mL). The combinedorganic layers were washed with water (15 mL), brine (15 mL), dried oversodium sulphate, filtered and concentrated. The resultant residue waspurified by Reveleris C-18 reversed phase column chromatography (50-55%acetonitrile in 0.1% aqueous formic acid to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(pyrimidin-4-yl)acetamide(55 mg, 0.12 mmol, 12% yield) as an off-white solid. MS (ESI) m/z 430.47[M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.81 (t, J=6.0 Hz,1H), 9.41 (s, 1H), 9.12 (d, J=5.1 Hz, 1H) 7.95 (dd, J=5.1, 1.5 Hz, 1H)7.71 (d, J=7.5 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J=7.5 Hz, 1H), 5.11 (dd,J=13.2, 5.1 Hz, 1H), 4.51 (d, J=6.3 Hz, 2H), 4.47 (d, J=17.6 Hz, 1H),4.32 (d, J=17.4 Hz, 1H) 2.96-2.88 (m, 1H), 2.63-2.57 (m, 1H), 2.43-2.38(m, 1H), 2.07-1.98 (m, 1H).

Example 118N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(piperidin-1-yl)ethoxy)phenyl)acetamide

A. Methyl 2,2-difluoro-2-(3-hydroxyphenyl)acetate

To a stirred solution of ethyl2,2-difluoro-2-(3-(methoxymethoxy)phenyl)acetate (13.0 g, 49.98 mmol) indichloromethane (130 mL) was added trifluoroacetic acid (65 mL) at 0° C.and stirred at room temperature for 5 h. The reaction mixture wasquenched with water (200 mL) and extracted with dichloromethane (3×200mL). The combined organic layers were washed with water (2×100 mL),brine (100 mL), dried over sodium sulphate and concentrated to affordmethyl 2,2-difluoro-2-(3-hydroxyphenyl)acetate (8.0 g, 37.03 mmol, 74%yield). GCMS (m/z) 216.1.

B. 1-(2-Chloroethyl)piperidine

To a stirred solution of 2-(piperidin-1-yl)ethanol (4.0 g, 30.95 mmol)in dichloromethane (40 mL) was added thionyl chloride (7.0 mL, 92.87) at0° C. and stirred at room temperature for 3 h. The reaction mixture wasquenched with water (50 mL) and extracted with dichloromethane (3×50mL). The combined organic layers were washed with water (2×50 mL), brine(50 mL), dried over sodium sulphate and concentrated to afford1-(2-chloroethyl)piperidine (1.8 g, 12.24 mmol, 40% yield). GCMS (m/z)147.1.

C. Ethyl 2,2-difluoro-2-(3-(2-(piperidin-1-yl)ethoxy)phenyl)acetate

To a stirred solution of methyl 2,2-difluoro-2-(3-hydroxyphenyl)acetate(1.0 g, 4.62 mmol) in acetone (15 mL) was added1-(2-chloroethyl)piperidine (885 mg, 6.01 mmol), potassium carbonate(1.9 g, 13.88 mmol) and stirred at 55° C. for 4 h. The reaction mixturewas filtered with celite bed) and wash with ethyl acetate (3×50 mL). Thefiltrate was dried over sodium sulphate and concentrated to afford ethyl2,2-difluoro-2-(3-(2-(piperidin-1-yl)ethoxy)phenyl)acetate (1.4 g, 4.28mmol, 93% yield). LCMS (ESI) m/z 328.0.

D. 2,2-Difluoro-2-(3-(2-(piperidin-1-yl)ethoxy)phenyl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(3-(2-(piperidin-1-yl)ethoxy)phenyl)acetate (1.4 g, 4.28mmol) in methanol-tetrahydrofuran-water mixture (20 mL, 1:1:1) was addedlithium hydroxide monohydrate (539 mg, 12.84 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous potassium bisulphate (20 mL)and extracted with ethyl acetate (2×40 mL). The combined organic layerswere washed with brine (20 mL), dried over sodium sulphate andconcentrated to afford2,2-difluoro-2-(3-(2-(piperidin-1-yl)ethoxy)phenyl)acetic acid (700 mg,2.34 mmol, 55% yield). LCMS (ESI) m/z 300.0.

E.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(piperidin-1-yl)ethoxy)phenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(3-(2-(piperidin-1-yl)ethoxy)phenyl)acetic acid (300 mg,1.00 mmol) and3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (310 mg, 1.00 mmol) in N,N-dimethylformamide (20 mL) wasadded N,N-diisopropylethylamine (389 mg, 3.01 mmol) followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (572 mg, 1.50 mmol) and stirred at roomtemperature for 4 h. The reaction mixture was diluted with water (50 mL)and extracted with ethyl acetate (2×40 mL). The combined organic layerswere washed with brine (30 mL), dried over sodium sulphate, concentratedand dried under vacuum. The product was purified by Reveleris C-18reversed phase column using 40% acetonitrile in aqueous formic acid(0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(piperidin-1-yl)ethoxy)phenyl)acetamide(56 mg, 0.09 mmol, 9% yield) as an off-white solid. LCMS (ESI) m/z555.23 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ (ppm) 10.99 (s, 1H), 9.66 (brt, J=5.9 Hz, 1H), 9.47 (br s, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.51 (t,J=8.1 Hz, 1H), 7.42 (s, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.27-7.12 (m, 3H),5.11 (br dd, J=5.1, 13.2 Hz, 1H), 4.56-4.21 (m, 6H), 3.61-3.45 (m, 4H),3.10-2.83 (m, 3H), 2.68-2.55 (m, 1H), 2.44-2.30 (m, 1H), 2.08-1.91 (m,1H), 1.90-1.60 (m, 5H), 1.50-1.30 (m, 1H).

Example 119N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-morpholinoethoxy)phenyl)acetamide

A. Ethyl 2,2-difluoro-2-(3-(2-morpholinoethoxy)phenyl)acetate

To a stirred solution of methyl 2,2-difluoro-2-(3-hydroxyphenyl)acetate(2.0 g, 9.25 mmol) in acetone (25 mL) was added4-(2-chloroethyl)morpholine hydrochloric acid (2.23 g, 12.03 mmol),potassium carbonate (3.83 g 27.77 mmol) and stirred at 55° C. for 16 h.The reaction mixture was quenched with water (50 mL) and extracted withethyl acetate (3×50 mL). The combined organic layers were washed withwater (2×20 mL), brine (30 mL), dried over sodium sulphate andconcentrated to afford ethyl2,2-difluoro-2-(3-(2-morpholinoethoxy)phenyl)acetate (1.5 g, 4.55 mmol,49% yield) as brown liquid. LCMS (ESI) m/z 330.0 [M+1]⁺.

B. 2,2-Difluoro-2-(3-(2-morpholinoethoxy)phenyl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(3-(2-morpholinoethoxy)phenyl)acetate (1.5 g, 4.55 mmol)in methanol/tetrahydrofuran/water mixture (20 mL, 1:1:1) was addedlithium hydroxide monohydrate (382 mg, 9.11 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was neutralized with 10% aqueous potassium bisulphate (20 mL)and extracted with ethyl acetate (2×40 mL). The combined organic layerswere washed with brine (20 mL), dried over sodium sulphate andconcentrated to afford 2,2-difluoro-2-(3-(morpholinoethoxy)phenyl)aceticacid (600 mg, 1.99 mmol, 44% yield) as a brown solid. LCMS (ESI) m/z302.0 [M+1]⁺.

C.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-morpholinoethoxy)phenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(3-(morpholinoethoxy)phenyl)acetic acid (513 mg, 1.66mmol) and 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (500 mg, 1.66 mmol) in N,N-dimethylformamide (20 mL) wasadded N,N-diisopropylethylamine (643.8 mg, 4.98 mmol) followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (946.4 mg, 2.49 mmol) and stirred at roomtemperature for 4 h. The reaction mixture was diluted with water (50 mL)and extracted with ethyl acetate (2×40 mL). The combined organic layerswere washed with brine (30 mL), dried over sodium sulphate, concentratedand dried under vacuum. The product was purified by Reveleris C-18reversed phase column using 40% acetonitrile in aqueous formic acid(0.1%) to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(morpholinoethoxy)phenyl)acetamidehydrochloride salt (40 mg, 0.07 mmol, 4.4% yield) as an off-white solid.LCMS (ESI) m/z 557.2 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.99 (s,1H), 10.17 (br s, 1H), 9.66 (br t, J=6.1 Hz, 1H), 7.68 (d, J=7.8 Hz,1H), 7.51 (t, J=8.1 Hz, 1H), 7.42 (s, 1H), 7.36 (d, J=7.8 Hz, 1H),7.25-7.15 (m, 3H), 5.11 (dd, J=4.9, 13.2 Hz, 1H), 4.48-4.37 (m, 5H),4.28 (d, J=17.2 Hz, 1H), 3.98 (br d, J=12.2 Hz, 2H), 3.73 (br t, J=11.7Hz, 2H), 3.64-3.49 (m, 5H), 3.48-3.22 (m, 2H), 2.98-2.84 (m, 1H),2.68-2.56 (m, 1H), 2.45-2.31 (m, 1H), 2.05-1.95 (m, 1H).

Example 1202-(3-(2-(4,4-Difluoropiperidin-1-yl)ethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

A. Ethyl 2-(4,4-difluoropiperidin-1-yl)acetate

To a stirred solution of 4,4-difluoropiperidine.hydrogenchloride (2 g,12.048 mmol) in tetrahydrofuran (45 mL) was added ethyl 2-bromoacetate(2.83 g, 18.07 mmol), triethyl amine (6.51 mL, 48.19 mmol) followed bytetrabutylammonium iodide (2.2 g, 6.024 mmol) at room temperature andallowed to stir at the same temperature for 16 h. The reaction wasquenched with ice water and extracted with ethyl acetate (3×30 mL). Thecombined organic layers were washed with brine (30 mL), dried oversodium sulfate, and concentrated to afford ethyl2-(4,4-difluoropiperidin-1-yl)acetate (1.5 g, 7.2 mmol, 60% yield) as acolourless liquid.GCMS (ESI) m/z 207 [M]⁺.

B. 2-(4,4-Difluoropiperidin-1-yl)ethanol

To a stirred solution of ethyl 2-(4,4-difluoropiperidin-1-yl)acetate (2g, 9.66 mmol) in tetrahydrofuran (15 mL) was added lithiumalluminiumhydride (9.6 mL, 19.32 mmol) at 0° C. and stirred at roomtemperature for 3 h. The reaction mixture was cooled to 0° C. andquenched with Celite/sodium sulphate.hydrate (4:1) and stirred at roomtemperature for 1 h. The white slurry was filtered through a Celite padand washed with thoroughly dichloromethane (60 mL). The filtrate wasdried over sodium sulphate and concentrated to afford2-(4,4-difluoropiperidin-1-yl)ethanol (1 g, 6.06 mmol, 62% yield) as acolourless liquid. ¹H NMR (300 MHz, DMSO-d₆) δ 4.45 (bs, 1H), 3.50 (t,J=5.6 Hz, 2H), 2.54-2.43 (m, 6H), 2.00-1.87 (m, 4H).

C. 2-(4,4-Difluoropiperidin-1-yl)ethyl methanesulfonate

To a solution of 2-(4,4-difluoropiperidin-1-yl)ethanol (1 g, 4.8 mmol)in tetrahydrofuran was added methane sulphonyl chloride (0.706 mL) at 0°C. and stirred at room temperature for 1 h. The reaction mixture wasquenched with aqueous sodium bicarbonate solution and extracted withethyl acetate (3×10 mL). The combined organic layers were washed withbrine (10 mL), dried over sodium sulfate, filtered and concentrated toafford 2-(4,4-difluoropiperidin-1-yl)ethyl methanesulfonate (800 mg,3.27 mmol, 54% yield) as a colourless liquid. Crude compound was used tothe next step without further purification.

D. tert-Butyl(3-iodophenoxy)dimethylsilane

To a stirred solution of 3-iodophenol (5 g, 22.7 mmol) inN,N-dimethylformamide (15 mL, 1:1:1) was added tert-butyldimethyl silylchloride (8.2 mL, 27.24 mmol) at 0° C. and stirred at room temperaturefor 16 h. The reaction mixture was poured into ice water (15 mL) andextracted with ethyl acetate (2×10 mL). The combined organic layers werewashed with brine (10 mL), dried over sodium sulfate, filtered andconcentrated to afford tert-butyl(3-iodophenoxy)dimethylsilane (10 g,17.96 mmol, 80% yield) as semi-solid compound which was taken to nextstep without further purification.

E. Ethyl 2,2-difluoro-2-(3-hydroxyphenyl)acetate

To a stirred solution of tert-butyl(3-iodophenoxy)dimethylsilane (10 g,22.33 mmol) in dimethylsulfoxide (75 mL) was added Copper powder (3.5 g,55.82 mmol) followed by ethyl 2-bromo-2,2-difluoroacetate (4.3 mL 33.49mmol) at room temperature and stirred at 55° C. for 16 h. The reactionmixture was poured into water (20 mL) and filtered through a Celite pad.The filtrate was extracted with ethylacetate (3×30 mL) and the combinedorganic layers were washed with brine (30 mL), dried over sodiumsulfate, filtered and concentrated to afford ethyl2,2-difluoro-2-(3-hydroxyphenyl)acetate (3.5 g, 16.20 mmol, 54% yield)as a colourless liquid. MS (ESI) m/z 215.34[M−1]⁺.

F. Ethyl2-(3-(2-(4,4-difluoropiperidin-1-yl)ethoxy)phenyl)-2,2-difluoroacetate

To a stirred solution of ethyl 2,2-difluoro-2-(3-hydroxyphenyl)acetate(700 mg, 2.86 mmol) in toluene (20 mL) was added2-(4,4-difluoropiperidin-1-yl)ethyl methanesulfonate (619 mg, 2.86 mmol)followed by potassium carbonate (1.59 g, 11.47 mmol), tetrabutylammoniumiodide (30 mg) at room temperature and allowed to stir at 110° C. for 16h. The reaction mixture was poured into ice water and extracted withethylacetate (3×30 mL). The combined organic layers were washed withbrine (30 mL), dried over sodium sulfate, filtered and concentrated toafford ethyl24342-(4,4-difluoropiperidin-1-yl)ethoxy)phenyl)-2,2-difluoroacetate(600 mg, 1.65 mmol, 60% yield) as a colourless liquid. MS (ESI) m/z364.14 [M+1]⁺.

G. 2-(3-(2-(4,4-Difluoropiperidin-1-yl)ethoxy)phenyl)-2,2-difluoroaceticacid

To a stirred solution of ethyl2-(3-(2-(4,4-difluoropiperidin-1-yl)ethoxy)phenyl)-2,2-difluoroacetate(1 g, 2.75 mmol) in tetrahydrofuran:methanol:water (15 mL, 1:1:1) wasadded lithium hydroxide monohydrate (348 mg, 8.26 mmol) and stirred atroom temperature for 3 h. The volatiles were removed under reducedpressure and obtained crude was dissolved in water (15 mL) and washedwith ethyl acetate (2×10 mL). The aqueous layer was acidified with 1Nhydrochloride solution and extracted with ethyl acetate (3×15 mL). Thecombined organic layers were washed with brine (10 mL), dried oversodium sulfate, filtered and concentrated to afford2-(3-(2-(4,4-difluoropiperidin-1-yl)ethoxy)phenyl)-2,2-difluoroaceticacid (800 mg, 2.38 mmol, 86% yield) as semi-solid compound. MS (ESI) m/z334.04 [M]⁺.

H.2-(3-(2-(4,4-Difluoropiperidin-1-yl)ethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

To a cold (0° C.) stirred solution of3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (276 mg, 0.895 mmol) and2-(3-(2-(4,4-difluoropiperidin-1-yl)ethoxy)phenyl)-2,2-difluoroaceticacid (300 mg, 0.895 mmol) in N,N-dimethylformamide (10 mL) was addedN,N-diisopropylethylamine (0.3 mL, 1.79 mmol) followed by1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (408 mg, 1.074 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was diluted with water (30 mL)and extracted with ethyl acetate (2×40 mL). The combined organic layerswere washed with brine (20 mL), dried over sodium sulfate andconcentrated. The crude compound was purified by Reveleris C-18 reversedphase column (60% acetonitrile/0.1% aqueous formic acid) to afford2-(3-(2-(4,4-difluoropiperidin-1-yl)ethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide(45 mg, 0.076 mmol, 8% yield) as an off-white solid. MS (ESI) m/z591.17. ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.61 (t, J=5.6 Hz,1H), 7.67 (d, J=8.0 Hz, 1H), 7.44 (dd, J=8.0, 7.6 Hz, 1H), 7.40 (s, 1H),7.36 (d, J=7.6 Hz, 1H), 7.16-7.11 (m, 3H), 5.10 (dd, J=13.2, 5.6 Hz,1H), 4.45 (d, J=6.0 Hz, 2H), 4.42 (d, J=17.8 Hz, 1H), 4.28 (d, J=17.2Hz, 1H), 4.09 (t, J=5.6 Hz, 2H), 2.95-2.87 (m, 1H), 2.78 (t, J=5.6 Hz,2H), 2.65-2.59 (m, 5H), 2.45-2.35 (m, 1H), 2.03-1.88 (m, 5H).

Example 121N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)acetamide

A. 4,5-Dichloro-2-methylpyridazin-3(2H)-one

To a stirred solution of 4,5-dichloropyridazin-3-ol (20 g, 0.121 mol) inN,N-dimethylformamide (100 mL) was added potassium carbonate (42 g,0.303 mol) followed by methyl iodide (18.9 g, 0.133 mol) and stirred atroom temperature for 2 h. The reaction mixture was filtered, to thefiltrate was added water (100 mL) and extracted with ethyl acetate(3×100 mL). The combined organic layers were washed with water (100 mL),brine (100 mL), dried over sodium sulphate and concentrated. Theresultant residue was purified by column chromatography (100-200 silica)using 10-20% ethyl acetate in hexanes to afford4,5-dichloro-2-methylpyridazin-3(2H)-one (15 g, 0.0837 mol, 69% yield).MS (ESI) m/z 179.03 [M+1]⁺.

B. 5-Iodo-2-methylpyridazin-3(2H)-one

To 4,5-dichloro-2-methylpyridazin-3(2H)-one (15 g, 83.79 mmol) was added47% of aqueous hydroiodic acid (185 mL) and stirred for 24 h at 140° C.To this reaction mixture was added aqueous saturated sodium thiosulphateand extracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with water (2×50 mL), brine (50 mL), dried over sodiumsulphate and concentrated. The resultant residue was purified by columnchromatography (100-200 silica) using 30-40% ethyl acetate in hexanes toafford 5-iodo-2-methylpyridazin-3(2H)-one (8.5 g, 36.016 mmol, 43%yield). MS (ESI) m/z 237.22 [M+1]⁺.

C. 1-tert-Butyl 3-ethyl2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)malonate

To a suspension of sodium hydride (2.07 g, 86.44 mmol) in 1,4-dioxane(85 mL) at 10° C. was added drop wise tert-butylethyl malonate (7 g,37.45 mmol) and allowed to warm to 25° C. over 1 h with stirring.5-Iodo-2-methylpyridazin-3(2H)-one (8.5 g, 36.016 mmol) was then addedportion wise at 25° C. and refluxed for 2 h. The reaction mixture wasdiluted with ice cold water (100 mL) and extracted with ethyl acetate(3×100 mL). The combined organic layers were washed with water (50 mL),brine (50 mL), dried over sodium sulphate and concentrated. Theresultant residue was purified by column chromatography (100-200 silica)using 20-30% ethyl acetate in hexanes to afford 1-tert-butyl 3-ethyl2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)malonate (7 g, 23.64 mmol,65% yield). MS (ESI) m/z 296.97 [M+1]⁺.

D. 1-tert-Butyl 3-ethyl2-fluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)malonate

To a solution of 1-tert-butyl 3-ethyl 2-(6-chloropyridazin-3-yl)malonate(7 g, 23.64 mmol) in tetrahydrofuran (100 mL) at 0° C. was added sodiumhydride (1.2 g, 25.77 mmol). The reaction was stirred for 15 min. Acloudy solution of SelectFluor (9.12 g, 25.77 mmol) inN,N-dimethylformamide (dry 20 mL) was added drop wise at 0° C. over aperiod of 10 min and allowed stir at room temperature for 2 h. Thereaction was quenched with ammonium chloride (50 mL) and extracted withethyl acetate (3×70 mL). The combined organic layers were washed withwater (50 mL), brine (50 mL), dried over sodium sulphate andconcentrated. The resultant residue was purified by columnchromatography (100-200 silica) using 25-35% ethyl acetate in hexanes toafford 1-tert-butyl 3-ethyl2-fluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)malonate (5 g,15.92 mmol, 67% yield). LCMS (ESI) m/z 315.40 [M+1]⁺.

E. Ethyl 2-fluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)acetate

A solution of 1-tert-butyl 3-ethyl2-fluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)malonate (5 g,15.92 mmol) in 25 mL trifluoroacetic acid/dichloromethane(1:1) wasstirred at room temperature for 4 h. To this reaction mixture was addedaqueous saturated sodium bicarbonate solution and extracted with ethylacetate (3×70 mL). The combined organic layers were washed with water(50 mL), brine (50 mL), dried over sodium sulphate and concentrated. Theresultant residue was purified by column chromatography (100-200 silica)using 25-35% ethyl acetate in hexanes to afford ethyl2-fluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)acetate (3 g, 32.71mmol, 88% yield). LCMS (ESI) m/z 215.13 [M+1]⁺.

F. Ethyl2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)acetate

To a solution of ethyl2-fluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)acetate (3 g, 32.71mmol) in dry tetrahydrofuran (30 mL) was added lithiumhexamethyldisilylazide (16.8 mL, 39.25 mmol) drop wise at −78° C. over aperiod of 10 min. After stirring for 15 min at same temperature, asolution of SelectFluor (5.9 g, 16.8 mmol) in dry N,N-dimethylformamide(10 mL) was added drop wise over 10 min. Upon complete addition, thereaction was allowed to warm to room temperature for 30 min withstirring and quenched with saturated ammonium chloride (50 mL). Afterevaporation of the organic fractions rotary evaporator, the reactionmixture was diluted with ice cold water (50 mL) and extracted with ethylacetate (5×50 mL). The combined organic layers were washed with water(30 mL), brine (30 mL), dried over sodium sulphate and concentrated. Theresultant residue was purified by CombiFlash column chromatography(100-200 silica) using 20-30% ethyl acetate in hexanes to afford ethyl2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)acetate (1.2 g,5.17 mmol, 36% yield). LCMS (ESI) m/z 233.39 [M+1]⁺.

G. 2,2-Difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)acetate (1.2 g,5.17 mmol) in 1,4-dioxane (36 mL) was added 3N aqueous hydrochloric acidsolution (24 mL) at 5° C. and stirred at room temperature for 16 h. Thereaction mixture was diluted with water (20 mL) and extracted with ethylacetate (2×30 mL). The combined organic layers were washed with water(20 mL), brine (20 mL), dried over sodium sulphate and concentrated toafford 2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)aceticacid (700 mg, 3.43 mmol, 66% yield) as off white solid. LCMS (ESI) m/z205.02 [M+1]⁺.

H.N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)acetic acid(197.6 mg, 0.968 mmol) in pyridine was added phosphoryl chloride (0.27mL, 2.906 mmol) drop wise and stirred at 0-5° C. for 1 h. To thisreaction mixture was then added3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (300 mg, 0.968 mmol) and stirred at room temperature for30 min. The reaction mixture was neutralized with aqueous saturatedsodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with water (2×10 mL), brine(10 mL), dried over sodium sulphate and concentrated. The resultantresidue was purified by Reveleris C-18 reversed phase columnchromatography using 40-60% acetonitrile in aqueous formic acid (0.1%)to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)acetamide(70 mg, 0.152 mmol, 15% yield) as an off white solid. MS (ESI) m/z459.16 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.98 (s, 1H) 9.80 (br t,J=5.66 Hz, 1H) 8.06 (d, J=2.19 Hz, 1H) 7.70 (d, J=7.68 Hz, 1H) 7.47 (s,1H) 7.40 (d, J=8.04 Hz, 1H) 7.15 (s, 1H) 5.11 (dd, J=13.16, 5.12 Hz, 1H)4.55-4.23 (m, 4H) 3.69 (s, 1H) 3.01-2.82 (m, 1H) 2.68-2.45 (m, 1H)2.46-2.31 (m, 1H) 2.06-1.93 (m, 1H).

Example 121N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(4-methylpiperazin-1-yl)phenyl)acetamide

A. Methyl 2-(3-bromophenyl)acetate

To a solution of 2-(3-bromophenyl)acetic acid (25 g, 116.27 mmol) indichloromethane (60 mL) were added oxalyl chloride (20 mL, 232.25 mmol)followed by N,N-dimethylformamide (1 mL) at 0° C. and stirred at roomtemperature for 1 h. The reaction mixture was concentrated, to thisresulting residue was added methanol (250 mL) and stirred at roomtemperature for 1 h. The reaction mass was concentrated, the resultingresidue was quenched with saturated aqueous sodium bicarbonate (250 mL)and extracted with ethyl acetate (3×200 mL). The combined organic layerswere washed with water (2×100 mL), brine (200 mL), dried over sodiumsulphate and concentrated methyl 2-(3-bromophenyl)acetate (20 g, 87.71mmol, 76% yield) as a colorless liquid. LCMS (ESI) m/z 270.29[M+42]⁺.(ACN adduct).

B. Ethyl 2-(3-(4-methylpiperazin-1-yl)phenyl)acetate

To a degassed solution of methyl 2-(3-bromophenyl)acetate (20 g, 87.71mmol) in toluene (250 mL) was added 1-methylpiperazine (10.52 g, 105.52mmol), cesium carbonate (40 g, 122.79 mmol) and degassed for 30 min. Tothis reaction mixture was then added2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (818 mg, 1.31 mmol),Palladium(II) acetate (590 mg, 0.877 mmol) and stirred at 110° C. for 16h. The reaction mixture was filtered through Celite pad, filtrate wasconcentrated, diluted with water (300 mL) and extracted with ethylacetate (3×200 mL). The combined organic layers were washed with water(200 mL) and brine (150 mL), dried over sodium sulphate, the organiclayer was concentrated under reduced pressure to get crude residue whichwas purified by CombiFlash column chromatography (100-200 silica) using21-24% methanol in dichloromethane to afford ethyl2-(3-(4-methylpiperazin-1-yl)phenyl)acetate (4.0 g, 16.12 mmol, 19%yield) as a brown colour solid. LCMS (ESI) m/z 249.26[M+1]⁺.

C. Ethyl 2,2-difluoro-2-(3-(4-methylpiperazin-1-yl)phenyl)acetate

To a solution of ethyl 2-(3-(4-methylpiperazin-1-yl)phenyl)acetate (4 g,16.12 mmol) in dry tetrahydrofuran (80 mL) was added lithiumhexamethyldisilazide (1M in tetrahydrofuran) (24 mL, 24.18 mmol)dropwise at −78° C. and stirred for 15 min. To this a solution ofN-fluorodibenzenesulfonimide (7.6 g, 24.18 mmol) in dry tetrahydrofuran(20 mL) was added drop wise over a period of 10 min. Upon completionaddition, the reaction was allowed to warm to room temperature over aperiod of 30 min and stirred for 1 h at room temperature. The reactionwas quenched with saturated ammonium chloride (50 mL) diluted with icecold water (100 mL) and extracted with ethyl acetate (2×200 mL). Thecombined organic layers were washed with brine (100 mL), dried oversodium sulphate and concentrated to afford ethyl2,2-difluoro-2-(3-(4-methylpiperazin-1-yl)phenyl)acetate (2.2 g, 8.87mmol) as a light brown color solid. LCMS (ESI) m/z 285.40 [M+1]⁺.

D. 2,2-Difluoro-2-(3-(4-methylpiperazin-1-yl)phenyl)acetic acid

To a cold (0° C.) stirred solution of ethyl2,2-difluoro-2-(3-(4-methylpiperazin-1-yl)phenyl)acetate (2.0 g, 7.04mmol) in tetrahydrofuran:methanol:water mixture (1:1:1, 30 mL) was addedlithium hydroxide monohydrate (504 mg, 21.12 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was diluted with water (50 mL) and washed with diethylether(2×50 mL). Aqueous layer neutralized with 10% aqueous potassiumbisulphate (15 mL) and put the lyophilization to give2,2-difluoro-2-(3-(4-methylpiperazin-1-yl)phenyl)acetic acid (1.2 g,4.44 mmol). LCMS (ESI) m/z 270.11[M+1]⁺.

E.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(4-methylpiperazin-1-yl)phenyl)acetamide

To a cold (0° C.) stirred solution of2,2-difluoro-2-(3-(4-methylpiperazin-1-yl)phenyl)acetic acid (524 mg,1.94 mmol) in pyridine (10 mL) was added phosphoryl chloride (0.45 mL,4.83 mmol) at 0-5° C. and stirred at same temperature for 1 h. Thenadded 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (500 mg, 1.61 mmol) and stirred at room temperature for 1h. The reaction mixture was concentrated. The resultant residue waspurified by PREP-HPLC ((Atlantis-T₃ column) using acetonitrile—0.1% ofammonium bicarbonate in water as eluent). After lyophilization LCMSindicated 84% of desired m/z, 16% of ring opened m/z was observed, whichwas further purified by CombiFlash column chromatography using 6-7%methanol in dichloromethane to affordN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)acetamide(35 mg, 0.067 mmol, 4% yield) as a off-white solid. LCMS (ESI) m/z526.39 [M+1]⁺. ¹H NMR (300 Mhz, DMSO-d₆) δ=11.00 (s, 1H), 9.59 (br t,J=6.1 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.45-7.29 (m, 3H), 7.11 (br d,J=8.4 Hz, 1H), 7.04 (s, 1H), 6.97 (br d, J=7.7 Hz, 1H), 5.11 (br dd,J=5.1, 13.2 Hz, 1H), 4.53-4.34 (m, 3H), 4.33-4.21 (m, 1H), 3.42-3.26 (m,4H), 3.14 (br s, 4H), 3.00-2.84 (m, 1H), 2.66-2.66 (m, 1H), 2.42-2.33(br dd, J=4.2, 13.0 Hz, 1H), 2.27 (br s, 3H), 2.06-1.92 (m, 1H).

Example 123 Effect of Test Compounds on KG-1 Cell Proliferation

The anti-proliferative activity of the test compound was evaluated onKG-1 cell line (American Type Culture Collection [ATCC]: cataloguenumber ATCC® CCL-246™) at 72 hours post-treatment. The seeding densityfor KG-1 was optimized to ensure assay linearity in 384-well plates.

Increasing concentrations of the test compound (0.5 nM to 10 μM) werespotted in a 10-point serial dilution fashion (3-fold dilution) induplicate via an acoustic dispenser (EDC ATS-100) into an empty 384-wellplate. The dimethyl sulfoxide (DMSO) concentration was kept constant fora final assay concentration of 0.1% DMSO. Prior to testing, KG-1 cellswere grown in RPMI-1640 (Roswell Park Memorial Institute—1640) mediumwith 10% FBS (fetal bovine serum: HyClone) and expanded in cultureflasks to provide sufficient amounts of starting material. Cells werethen diluted to 5000 cells per well, in a 50 μL volume and addeddirectly to the compound-spotted 384-well plates. Cells were allowed togrow for 72 hours in 5% CO₂ at 37° C. At the time when exposure of cellsto compound began (to), initial viable cell number was assessed via CellTiter-Glo® Luminescent Cell Viability Assay at a 1 vol: 2 vol ratioaccording to manufacturer's instructions (Promega Corporation, Madison,Wis.) by quantifying the level of luminescence generated byadenosine-5′-triphosphate (ATP) present in viable cells. After 72 hours,cell viability of t-treated cells was assessed via Cell Titer-Glo® andread for luminescence. IC₅₀ values for exemplary compounds are providedin Table 1.

In Table 1, IC₅₀ values as provided as below:

A: <0.01 μM; B: 0.01 to 0.05 μM; C: >0.05 μM to 0.1 μM; and D: >0.1 μMto 10 μM.

TABLE 1 FCA Prolif Cell TiterGlo KG-1 Cpd 72 h No. Compound Name MH+(IC₅₀) 1

2-(3-chloro-4-methylphenyl)- N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)-2,2- difluoroacetamide 476.2 B 2

2-(4-chlorophenyl)-N-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 462.0 B 3

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4- methoxyphenyl)acetamide 458.2 D 4

2-(3-chlorophenyl)-N-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 462.2 B 5

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4- fluorophenyl)acetamide 446.2 B 6

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-p- tolylacetamide 442.2 B 7

2-(3,4-dichlorophenyl)-N-((2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 498.0 B 8

2-(2-chlorophenyl)-N-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 462.0 D 9

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2- (trifluoromethyl)phenyl)acetamide NA B 10

2-(4-tert-butylphenyl)-N-((2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 484.0 A 11

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2- phenylacetamide 428.2 C 12

2-(3-chloro-4-fluorophenyl)-N- ((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 480.0 B 13

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4- (trifluoromethylthio)phenyl)acetamide528.1 D 14

2-(2,6-difluorophenyl)-N-((2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 464.2 D 15

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-o- tolylacetamide 442.2 B 16

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2- fluorophenyl)acetamide 446.2 C 17

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxyphenyl)- 2,2-difluoroacetamide 472.2 B 18

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2- (trifluoromethoxy)phenyl)acetamide 512.2 B19

2-(3-bromo-4- (trifluoromethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide 592.0 B 20

2-(3-chloro-4-methoxyphenyl)- N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)-2,2- difluoroacetamide 492.5 D 21

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-m- tolylacetamide 442.3 B 22

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4- isopropoxyphenyl)acetamide 486.1 B 23

2-(3,4-difluorophenyl)-N-((2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 464.0 D 24

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3- fluorophenyl)acetamide 446.0 D 25

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3- (trifluoromethyl)pyridin-2- yl)acetamide497.4 C 26

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4- isopropylphenyl)acetamide 470.2 A 27

2-(2,4-dichlorophenyl)-N-((2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 496.0 C 28

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2- methoxyphenyl)acetamide 458.2 D 29

2-(4-cyclopropylphenyl)-N-((2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 468.1 C 30

2-(4-chloro-2-fluorophenyl)-N- ((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 480.1 A 31

2-(4-chloro-3-fluorophenyl)-N- ((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 480.1 B 32

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3- fluoro-2- methylphenyl)acetamide 460.1 B33

2-(3-chloro-2-methylphenyl)- N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)-2,2- difluoroacetamide 476.1 A 34

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4- fluoro-2-(trifluoromethyl)phenyl)acetamide 514.1 B 35

2-(4-chloro-2-methylphenyl)- N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)-2,2- difluoroacetamide 476.1 B 36

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4- fluoro-2- methylphenyl)acetamide 460.1 B37

2-(4-chloro-2- (trifluoromethyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide 530.1 B 38

2-cyclohexyl-N-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 434.1 B 39

2-(4-chloro-2- (trifluoromethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide 546.0 A 40

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro- 2-(3-(2- methoxyethoxy)phenyl)acetamide 502.0 C41

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro- 2-(3-(2- hydroxyethoxy)phenyl)acetamide 488.1 D42

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro- 2-(4-(2- methoxyethoxy)phenyl)acetamide 502.1 D43

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro- 2-(3-(2- hydroxyethyl)phenyl)acetamide 472.1 D44

2-(3-(dimethylamino)phenyl)- N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)-2,2- difluoroacetamide 470.8 B 45

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3- (piperidin-1- yl)phenyl)acetamide 510.8 A46

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3- morpholinophenyl)acetamide 513.0 D 47

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4- fluoro-2- isopropoxyphenyl)acetamide 504.0A 48

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2- (2,2,2- trifluoroethoxy)phenyl)acetamide525.9 B 49

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-4- fluorophenyl)-2,2- difluoroacetamide 490.0 B50

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2- isopropoxyphenyl)acetamide 486.0 A 51

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2- fluoro-4- isopropoxyphenyl)acetamide 504.0B 52

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3- (morpholinomethyl)phenyl)acetamide 527.0 D53

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4- fluoro-2-(2,2,2-trifluoroethoxy)phenyl)acetamide 544.0 A 54

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4- isopropoxy-2- methylphenyl)acetamide 500.2A 55

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4- isopropoxy-3- methylphenyl)acetamide 500.6B 56

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3- fluoro-4- isopropoxyphenyl)acetamide 504.6D 57

2-(3-chloro-4- isopropoxyphenyl)-N-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 520.0 B 58

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2- methyl-4-(trifluoromethoxy)phenyl)acetamide 526.5 B 59

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2- fluoro-4-(trifluoromethoxy)phenyl)acetamide 529.6 D 60

2-(5-chloropyridin-2-yl)-N-((2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 462.7 C 61

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5- fluoropyridin-2-yl)acetamide 446.7 D 62

2-(2,4-difluorophenyl)-N-((2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 463.7 B 63

2-(4-bromophenyl)-N-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 505.6 C 64

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro- 2-(2-(2- methoxyethoxy)phenyl)acetamide 502.3 B65

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1- hydroxycyclohexyl)acetamide 450.2 B 66

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1- hydroxycyclopentyl)acetamide 436.2 D 67

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3- methyl-4-(trifluoromethoxy)phenyl)acetamide 526.3 D 68

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2-(3-ethoxypyridin- 2-yl)-2,2-difluoroacetamide 473.3 D 69

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3- methylpyridin-2-yl)acetamide 443.3 B 70

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5- methylpyridin-2-yl)acetamide 443.3 D 71

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-6- fluorophenyl)-2,2- difluoroacetamide 490.3 A72

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4′- fluorobiphenyl-4-yl)acetamide 522.5 D 73

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-5- fluorophenyl)-2,2- difluoroacetamide 490.1 D74

2-cyclopentyl-N-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 420.2 D 75

2-(3-chloro-4- (trifluoromethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide 546.3 D 76

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4- methoxy-2-(trifluoromethyl)phenyl)acetamide 526.2 A 77

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro- 2-(2-(2- hydroxyethoxy)phenyl)acetamide 488.1 D78

2-(4-chloro-2-ethoxyphenyl)- N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)-2,2- difluoroacetamide 506.1 C 79

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2- hydroxyphenyl)acetamide 444.4 A 80

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2- (methylamino)phenyl)acetamide 457.2 A 81

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4- isopropoxy-2-(trifluoromethyl)phenyl)acetamide 554.0 A 82

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4- methylcyclohexyl)acetamide 448.2 A 83

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro- 2-(3-(2- isopropoxyethoxy)phenyl)acetamide529.9 A 84

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3- hydroxyphenyl)acetamide 444.1 D 85

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3- ((4-methylpiperazin-1-yl)methyl)phenyl)acetamide 540.4 D 86

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro- 2-(4-methyl-2-(trifluoromethyl)phenyl)acetamide 510.3 A 87

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro- 2-(3-(2-(2- methoxyethoxy)ethoxy)phenyl)acetamide 546.1 D 88

2-(3-(2- (dimethylamino)ethoxy)phenyl)- N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)-2,2- difluoroacetamide 515.1 D 89

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5- isopropylpyridin-2- yl)acetamide 471.1 C90

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro- 2-(3-(2- (methylsulfonyl)ethoxy)phenyl)acetamide 549.8 D 91

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro- 2-(3-(3- (methylsulfonyl)propyl)phenyl)acetamide 548.0 D 92

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4- (2-fluoropropan-2- yl)phenyl)acetamide486.2 C 93

2-(1-benzyl-6-oxo-1,6- dihydropyridin-3-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide 535.1 D 94

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5- methoxypyridin-2-yl)acetamide 459.2 D 95

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1- methyl-6-oxo-1,6-dihydropyridin-3-yl)acetamide 459.2 D 96

2-(5-tert-butylpyridin-2-yl)-N- ((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 485.2 B 97

2-(5-cyclopropylpyridin-2-yl)- N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)-2,2- difluoroacetamide 469.1 D 98

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5- isopropoxypyridin-2- yl)acetamide 487.2 D99

2-(5-bromopyridin-2-yl)-N-((2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 507.8 D 100

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4- fluoro-2-(trifluoromethoxy)phenyl)acetamide 530.1 C 101

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4- fluorocyclohexyl)acetamide 452.2 D 102

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4- (methylsulfonyl)phenyl)acetamide 506.1 D103

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3- (methylsulfonyl)phenyl)acetamide 506.0 D104

2-(2-aminopyrimidin-5-yl)-N- ((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 445.4 D 105

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5- (trifluoromethylthio)pyridin-2-yl)acetamide 529.0 D 106

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro- 2-(3-(2- (methylamino)ethoxy)phenyl)acetamide501.6 D 107

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1- methyl-6-oxo-1,6- dihydropyridazin-3-yl)acetamide 460.5 D 108

2-(2-aminopyrimidin-4-yl)-N- ((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2- difluoroacetamide 445.1 D 109

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2- (pyrimidin-4-yl)acetamide 430.5 D 110

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3- (2-(piperidin-1-yl)ethoxy)phenyl)acetamide 555.2 D 111

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro- 2-(3-(2- morpholinoethoxy)phenyl)acetamide557.2 D 112

2-(3-(2-(4,4-difluoropiperidin- 1-yl)ethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide 591.2 C 113

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1- methyl-6-oxo-1,6- dihydropyridazin-4-yl)acetamide 459.2 D 114

N-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3- (4-methylpiperazin-1- yl)phenyl)acetamide526.4 D

The embodiments described above are intended to be merely exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the invention and are encompassedby the appended claims.

Compounds of the invention are for use in medicine.

Compounds of the invention are for use in the methods of treatmentprovided herein.

What is claimed is:
 1. A method of treating a solid tumor comprisingadministering to a mammal having a solid tumor a therapeuticallyeffective amount of a compound of Formula I:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein: R¹ is optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted heterocyclyl; R² and R³ are eachhalo; where the substituents on R¹, when present, are one to threegroups Q, where each Q is independently alkyl, halo, haloalkyl,alkoxyalkyl, oxo, hydroxyl, alkoxy, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, —R⁴OR⁵,—R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷), —R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷),—R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸; each R⁴ is independentlyalkylene, alkenylene or a direct bond; each R⁵ is independentlyhydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl or heterocyclylalkyl, where alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl orheterocyclylalkyl groups in R⁵ are each independently optionallysubstituted with 1-3 Q¹ groups, where each Q¹ is independently alkyl,haloalkyl or halo; R⁶ and R⁷ are selected as follows: i) R⁶ and R⁷ areeach independently hydrogen or alkyl; or ii) R⁶ and R⁷ together with thenitrogen atom on which they are substituted form a 5 or 6-memberedheterocyclyl or heteroaryl ring, optionally substituted with one or twohalo, alkyl or haloalkyl; R⁸ is alkyl, haloalkyl, or hydroxyalkyl; R⁹ isalkyl or aryl; J is O or S; and t is 1 or
 2. 2. The method of claim 1,wherein R¹ is optionally substituted cycloalkyl, optionally substitutedaryl, optionally substituted heteroaryl or optionally substitutedheterocyclyl.
 3. The method of claim 1 having Formula II:

or an enantiomer or a mixture or enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein: R¹ is optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted heterocyclyl; where thesubstituents on R¹, when present, are one to three groups Q, where eachQ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, —R⁴OR⁵, —R⁴SR⁵, —R⁴N(R⁶)(R⁷),R⁴OR⁴N(R⁶)(R⁷) or R⁴OR⁴C(J)N(R⁶)(R⁷); J is O or S; each R⁴ isindependently alkylene, alkenylene or a direct bond; each R⁵ isindependently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and R⁶ and R⁷are selected as follows: i) R⁶ and R⁷ are each independently hydrogen oralkyl; or ii) R⁶ and R⁷ together with the nitrogen atom on which theyare substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl.
 4. Themethod of claim 1, wherein R¹ is optionally substituted aryl; where thesubstituents on R¹, when present, are one to three groups Q, where eachQ is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, —R⁴OR⁵, —R⁴SR⁵, —R⁴N(R⁶)(R⁷),R⁴OR⁴N(R⁶)(R⁷) or R⁴OR⁴C(J)N(R⁶)(R⁷); J is O or S; each R⁴ isindependently alkylene, alkenylene or a direct bond; each R⁵ isindependently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and R⁶ and R⁷are selected as follows: i) R⁶ and R⁷ are each independently hydrogen oralkyl; or ii) R⁶ and R⁷ together with the nitrogen atom on which theyare substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring,optionally substituted with one or two halo, alkyl or haloalkyl.
 5. Themethod of claim 1, wherein R¹ is optionally substituted phenyl,optionally substituted cyclohexyl, optionally substituted piperidinyl,or optionally substituted pyridyl, where the substituents on R¹, whenpresent, are one to three groups Q, where each Q is independently halo,alkyl, —R⁴OR⁵ or —R⁴N(R⁶)(R⁷); each R⁴ is independently a direct bond oralkylene; each R⁵ is independently hydrogen, halo, alkyl, alkoxy,haloalkoxy or haloalkyl; and R⁶ and R⁷ are selected as follows: i) R⁶and R⁷ are each independently hydrogen or alkyl; or ii) R⁶ and R⁷together with the nitrogen atom on which they are substituted form a 5or 6-membered heterocyclyl ring.
 6. The method of claim 1, wherein R¹ isoptionally substituted phenyl, where the substituents on R¹, whenpresent, are one to three groups Q, where each Q is independentlyfluoro, chloro, methyl, tert butyl, —R⁴OR⁵, —R⁴SR⁵ orR⁴OR⁴C(J)N(R⁶)(R⁷); each R⁴ is independently a direct bond or methylene;each R⁵ is independently hydrogen, methyl, ethyl or trifluoromethyl; andR⁶ and R⁷ are each independently hydrogen or methyl.
 7. The method ofclaim 1, wherein the compound has formula III

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein: each Q¹ is independentlyalkyl, halo, haloalkyl, alkoxyalkyl, hydroxyl, alkoxy, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, —R⁴OR⁵, —R⁴SR⁵, —R⁴N(R⁶)(R⁷),R⁴OR⁴N(R⁶)(R⁷) or R⁴OR⁴C(J)N(R⁶)(R⁷); J is O or S; each R⁴ isindependently alkylene, alkenylene or a direct bond; each R⁵ isindependently hydrogen, alkyl, halo, alkoxy, haloalkyl or hydroxyalkyl;R⁶ and R⁷ are selected as follows: i) R⁶ and R⁷ are each independentlyhydrogen or alkyl; or ii) R⁶ and R⁷ together with the nitrogen atom onwhich they are substituted form a 5 or 6-membered heterocyclyl orheteroaryl ring, optionally substituted with one or two halo, alkyl orhaloalkyl; and n is 0-3.
 8. The method of claim 1, wherein the compoundhas formula IV

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein: Q² is hydrogen, alkyl, halo,haloalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,—R⁴OR⁵, —R⁴SR⁵, —R⁴N(R⁶)(R⁷), R⁴OR⁴N(R⁶)(R⁷) or R⁴OR⁴C(J)N(R⁶)(R⁷); J isO or S; each R⁴ is independently alkylene, alkenylene or a direct bond;each R⁵ is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; andR⁶ and R⁷ are each independently hydrogen or alkyl.
 9. The method ofclaim 1, wherein the compound has formula V

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein: Q³ and Q⁴ are eachindependently hydrogen, alkyl, halo, haloalkyl, hydroxyl, alkoxy,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, —R⁴OR⁵, —R⁴SR⁵, —R⁴N(R⁶)(R⁷), R⁴OR⁴N(R⁶)(R⁷) orR⁴OR⁴C(J)N(R⁶)(R⁷); J is O or S; each R⁴ is independently alkylene,alkenylene or a direct bond; each R⁵ is independently hydrogen, alkyl,haloalkyl, hydroxyalkyl, or alkoxyalkyl; and R⁶ and R⁷ are eachindependently hydrogen or alkyl.
 10. The method of claim 1, wherein thecompound has formula VI

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein: Q⁴ and Q⁵ are eachindependently hydrogen, alkyl, halo, haloalkyl, hydroxyl, alkoxy,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, —R⁴OR⁵, —R⁴SR⁵, —R⁴N(R⁶)(R⁷), R⁴OR⁴N(R⁶)(R⁷) orR⁴OR⁴C(J)N(R⁶)(R⁷); J is O or S; each R⁴ is independently alkylene,alkenylene or a direct bond; each R⁵ is independently hydrogen, alkyl,haloalkyl, alkoxyalkyl or hydroxyalkyl; and R⁶ and R⁷ are selected asfollows: i) R⁶ and R⁷ are each independently hydrogen or alkyl; or ii)R⁶ and R⁷ together with the nitrogen atom on which they are substitutedform a 5 or 6-membered heterocyclyl or heteroaryl ring, optionallysubstituted with one or two halo, alkyl or haloalkyl.
 11. The method ofclaim 10, wherein Q⁴ and Q⁵ are each independently hydrogen, halo,alkyl, alkoxyalkyl, —R⁴N(R⁶)(R⁷), or —R⁴OR⁵; R⁴ is a direct bond oralkylene; R⁵ is hydrogen, alkyl or haloalkyl; and R⁶ and R⁷ togetherwith the nitrogen atom on which they are substituted form a 6-memberedheterocyclyl.
 12. The method of claim 1, wherein the compound hasformula VII

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein: Q⁵ is hydrogen, alkyl, halo,haloalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, —R⁴OR⁵, —R⁴SR⁵, —R⁴N(R⁶)(R⁷),R⁴OR⁴N(R⁶)(R⁷) or R⁴OR⁴C(J)N(R⁶)(R⁷); J is O or S; each R⁴ isindependently alkylene, alkenylene or a direct bond; each R⁵ isindependently hydrogen, alkyl, haloalkyl, alkoxyalkyl or hydroxyalkyl;and R⁶ and R⁷ are selected as follows: i) R⁶ and R⁷ are eachindependently hydrogen or alkyl; or ii) R⁶ and R⁷ together with thenitrogen atom on which they are substituted form a 5 or 6-memberedheterocyclyl or heteroaryl ring, optionally substituted with one or twohalo, alkyl or haloalkyl.
 13. The method of claim 12, wherein Q⁵ ishydrogen, halo, alkyl, alkoxyalkyl, —R⁴N(R⁶)(R⁷) or —R⁴OR⁵; R⁴ is adirect bond or alkylene; and R⁵ is hydrogen, alkyl or haloalkyl; and R⁶and R⁷ together with the nitrogen atom on which they are substitutedform a 6-membered heterocyclyl.
 14. The method of claim 1, wherein thecompound has formula VIII

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein: Q² and Q⁵ are eachindependently hydrogen, alkyl, halo, haloalkyl, hydroxyl, alkoxy,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, —R⁴OR⁵, —R⁴SR⁵,—R⁴N(R⁶)(R⁷), R⁴OR⁴N(R⁶)(R⁷) or R⁴OR⁴C(J)N(R⁶)(R⁷); J is O or S; each R⁴is independently alkylene, alkenylene or a direct bond; each R⁵ isindependently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and R⁶ and R⁷are each independently hydrogen or alkyl, or R⁶ and R⁷ together with thenitrogen atom on which they are substituted form a 6-memberedheterocyclyl.
 15. The method claim 14, wherein Q² and Q⁵ are eachindependently hydrogen, halo, alkyl, alkoxyalkyl, optionally substitutedaryl, or —R⁴OR⁵; R⁴ is a direct bond or alkylene; and R⁵ is hydrogen,alkyl or haloalkyl.
 16. The method of claim 1, wherein the compound isselected from2-(3-chloro-4-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methoxyphenyl)acetamide;2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluorophenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-p-tolylacetamide;2-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(2-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(trifluoromethyl)phenyl)acetamide;2-(4-tert-butylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-phenylacetamide2-(3-chloro-4-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(trifluoromethylthio)phenyl)acetamide;2-(2,6-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-o-tolylacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-fluorophenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxyphenyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(trifluoromethoxy)phenyl)acetamide;2-(3-bromo-4-(trifluoromethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(3-chloro-4-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-m-tolylacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxyphenyl)acetamide;2-(3,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-fluorophenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(trifluoromethyl)pyridin-2-yl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropylphenyl)acetamide;2-(2,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-methoxyphenyl)acetamide;2-(4-cyclopropylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(4-chloro-2-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(4-chloro-3-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-fluoro-2-methylphenyl)acetamide;2-(3-chloro-2-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-(trifluoromethyl)phenyl)acetamide;2-(4-chloro-2-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-methylphenyl)acetamide;2-(4-chloro-2-(trifluoromethyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-cyclohexyl-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(4-chloro-2-(trifluoromethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-methoxyethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-hydroxyethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(2-methoxyethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-hydroxyethyl)phenyl)acetamide;2-(3-(dimethylamino)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(piperidin-1-yl)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-morpholinophenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-isopropoxyphenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2,2,2-trifluoroethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-4-fluorophenyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-isopropoxyphenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-fluoro-4-isopropoxyphenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(morpholinomethyl)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxy-2-methylphenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxy-3-methylphenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-fluoro-4-isopropoxyphenyl)acetamide;2-(3-chloro-4-isopropoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-methyl-4-(trifluoromethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-fluoro-4-(trifluoromethoxy)phenyl)acetamide;2-(5-chloropyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-fluoropyridin-2-yl)acetamide;2-(2,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(4-bromophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2-methoxyethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-hydroxycyclohexyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-hydroxycyclopentyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-methyl-4-(trifluoromethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(3-ethoxypyridin-2-yl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-methylpyridin-2-yl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-methylpyridin-2-yl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-6-fluorophenyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4′-fluorobiphenyl-4-yl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-5-fluorophenyl)-2,2-difluoroacetamide;2-cyclopentyl-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(3-chloro-4-(trifluoromethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2-hydroxyethoxy)phenyl)acetamide;2-(4-chloro-2-ethoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-hydroxyphenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(methylamino)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxy-2-(trifluoromethyl)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methylcyclohexyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-isopropoxyethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-hydroxyphenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methyl-2-(trifluoromethyl)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)acetamide;2-(3-(2-(dimethylamino)ethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-isopropylpyridin-2-yl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(methylsulfonyl)ethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(3-(methylsulfonyl)propyl)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(2-fluoropropan-2-yl)phenyl)acetamide;2-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-methoxypyridin-2-yl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetamide;2-(5-tert-butylpyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(5-cyclopropylpyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-isopropoxypyridin-2-yl)acetamide;2-(5-bromopyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-(trifluoromethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluorocyclohexyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(methylsulfonyl)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(methylsulfonyl)phenyl)acetamide;2-(2-aminopyrimidin-5-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-(trifluoromethylthio)pyridin-2-yl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(methylamino)ethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)acetamide;2-(2-aminopyrimidin-4-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(pyrimidin-4-yl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(piperidin-1-yl)ethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-morpholinoethoxy)phenyl)acetamide;2-(3-(2-(4,4-difluoropiperidin-1-yl)ethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)acetamide;andN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(4-methylpiperazin-1-yl)phenyl)acetamide,or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof.
 21. The method of claim 1, wherein thecompound is selected fromN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methoxyphenyl)acetamide;2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluorophenyl)acetamide;and2-(2-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamideor an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof.
 22. The method of claim 1, wherein thecompound isN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methoxyphenyl)acetamideor an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof.
 23. The method of claim 1, wherein thecompound is2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamideor an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof.
 24. The method of claim 1, wherein thecompound is2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamideor an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof.
 25. The method of claim 1, wherein thecompound isN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluorophenyl)acetamideor an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof.
 26. The method of claim 1, wherein thecompound is2-(2-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamideor an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof.
 27. The method of claim 1, wherein thetumor is a tumor of bladder, bone, blood, brain, breast, cervix, chest,colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes,lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis,throat, or uterus.
 28. The method of claim 1, wherein the tumor ismetastatic.
 29. The method of claim 1, wherein the tumor isdrug-resistant.
 30. The method of claim 1, further comprisingadministering a therapeutically effective amount of a second activeagent or a support care therapy.
 31. The method of claim 30, wherein thesecond active agent is a therapeutic antibody that specifically binds toa cancer antigen, a hematopoietic growth factor, a cytokine, ananti-cancer agent, an antibiotic, a cox-2 inhibitor, an immunomodulatoryagent, an immunosuppressive agent, a corticosteroid or apharmacologically active mutant or derivative thereof.
 32. A method fortreating a disease selected from amyloidosis, neuroblastoma, meningioma,hemangiopericytoma, multiple brain metastases, glioblastoma multiforme,glioblastoma, brain stem glioma, poor prognosis malignant brain tumor,malignant glioma, recurrent malignant glioma, anaplastic astrocytoma,anaplastic oligodendroglioma, neuroendocrine tumor, rectaladenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectalcarcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma,karotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin'slymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuselarge B-Cell lymphoma, low grade follicular lymphoma, malignantmelanoma, malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneousvasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressive, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unrescectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen independentprostate cancer, androgen dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, and leiomyoma, wherein themethod comprises administering to a mammal having the disease atherapeutically effective amount of a compound of Formula I:

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein: R¹ is optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted heterocyclyl; R² and R³ are eachhalo; where the substituents on R¹, when present, are one to threegroups Q, where each Q is independently alkyl, halo, haloalkyl,alkoxyalkyl, oxo, hydroxyl, alkoxy, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, —R⁴OR⁵,—R⁴OR⁵—R⁴OR⁵, —R⁴N(R⁶)(R⁷), —R⁴SR⁵, —R⁴OR⁴N(R⁶)(R⁷),—R⁴OR⁴C(J)N(R⁶)(R⁷), —C(J)R⁹ or R⁴S(O)_(t)R⁸; each R⁴ is independentlyalkylene, alkenylene or a direct bond; each R⁵ is independentlyhydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl or heterocyclylalkyl, where alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl orheterocyclylalkyl groups in R⁵ are each independently optionallysubstituted with 1-3 Q¹ groups, where each Q¹ is independently alkyl,haloalkyl or halo; R⁶ and R⁷ are selected as follows: i) R⁶ and R⁷ areeach independently hydrogen or alkyl; or ii) R⁶ and R⁷ together with thenitrogen atom on which they are substituted form a 5 or 6-memberedheterocyclyl or heteroaryl ring, optionally substituted with one or twohalo, alkyl or haloalkyl; R⁸ is alkyl, haloalkyl, or hydroxyalkyl; R⁹ isalkyl or aryl; J is O or S; and t is 1 or
 2. 33. The method of claim 32,wherein the compound has formula VIII

or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof, wherein: Q² and Q⁵ are eachindependently hydrogen, alkyl, halo, haloalkyl, hydroxyl, alkoxy,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, —R⁴OR⁵, —R⁴SR⁵,—R⁴N(R⁶)(R⁷), R⁴OR⁴N(R⁶)(R⁷) or R⁴OR⁴C(J)N(R⁶)(R⁷); J is O or S; each R⁴is independently alkylene, alkenylene or a direct bond; each R⁵ isindependently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and R⁶ and R⁷are each independently hydrogen or alkyl, or R⁶ and R⁷ together with thenitrogen atom on which they are substituted form a 6-memberedheterocyclyl.
 34. The method of claim 32, wherein the compound isselected from2-(3-chloro-4-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methoxyphenyl)acetamide;2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluorophenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-p-tolylacetamide;2-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(2-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(trifluoromethyl)phenyl)acetamide;2-(4-tert-butylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-phenylacetamide2-(3-chloro-4-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(trifluoromethylthio)phenyl)acetamide;2-(2,6-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-o-tolylacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-fluorophenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxyphenyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(trifluoromethoxy)phenyl)acetamide;2-(3-bromo-4-(trifluoromethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(3-chloro-4-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-m-tolylacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxyphenyl)acetamide;2-(3,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-fluorophenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(trifluoromethyl)pyridin-2-yl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropylphenyl)acetamide;2-(2,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-methoxyphenyl)acetamide;2-(4-cyclopropylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(4-chloro-2-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(4-chloro-3-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-fluoro-2-methylphenyl)acetamide;2-(3-chloro-2-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-(trifluoromethyl)phenyl)acetamide;2-(4-chloro-2-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-methylphenyl)acetamide;2-(4-chloro-2-(trifluoromethyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-cyclohexyl-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(4-chloro-2-(trifluoromethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-methoxyethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-hydroxyethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(2-methoxyethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-hydroxyethyl)phenyl)acetamide;2-(3-(dimethylamino)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(piperidin-1-yl)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-morpholinophenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-isopropoxyphenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2,2,2-trifluoroethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-4-fluorophenyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-isopropoxyphenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-fluoro-4-isopropoxyphenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(morpholinomethyl)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxy-2-methylphenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxy-3-methylphenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-fluoro-4-isopropoxyphenyl)acetamide;2-(3-chloro-4-isopropoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-methyl-4-(trifluoromethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-fluoro-4-(trifluoromethoxy)phenyl)acetamide;2-(5-chloropyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-fluoropyridin-2-yl)acetamide;2-(2,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(4-bromophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2-methoxyethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-hydroxycyclohexyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-hydroxycyclopentyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-methyl-4-(trifluoromethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(3-ethoxypyridin-2-yl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-methylpyridin-2-yl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-methylpyridin-2-yl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-6-fluorophenyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4′-fluorobiphenyl-4-yl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-ethoxy-5-fluorophenyl)-2,2-difluoroacetamide;2-cyclopentyl-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(3-chloro-4-(trifluoromethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(2-hydroxyethoxy)phenyl)acetamide;2-(4-chloro-2-ethoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-hydroxyphenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(2-(methylamino)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-isopropoxy-2-(trifluoromethyl)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methylcyclohexyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-isopropoxyethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-hydroxyphenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methyl-2-(trifluoromethyl)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)acetamide;2-(3-(2-(dimethylamino)ethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-isopropylpyridin-2-yl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(methylsulfonyl)ethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(3-(methylsulfonyl)propyl)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(2-fluoropropan-2-yl)phenyl)acetamide;2-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-methoxypyridin-2-yl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetamide;2-(5-tert-butylpyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(5-cyclopropylpyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-isopropoxypyridin-2-yl)acetamide;2-(5-bromopyridin-2-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluoro-2-(trifluoromethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluorocyclohexyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(methylsulfonyl)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(methylsulfonyl)phenyl)acetamide;2-(2-aminopyrimidin-5-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(5-(trifluoromethylthio)pyridin-2-yl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(methylamino)ethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)acetamide;2-(2-aminopyrimidin-4-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(pyrimidin-4-yl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-(piperidin-1-yl)ethoxy)phenyl)acetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(2-morpholinoethoxy)phenyl)acetamide;2-(3-(2-(4,4-difluoropiperidin-1-yl)ethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)acetamide;andN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(3-(4-methylpiperazin-1-yl)phenyl)acetamide,or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof.
 35. The method of claim 32, wherein thecompound is selected fromN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methoxyphenyl)acetamide;2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluorophenyl)acetamide;and2-(2-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamideor an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof.
 36. The method of claim 32, wherein thecompound isN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-methoxyphenyl)acetamideor an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof.
 37. The method of claim 32, wherein thecompound is2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamideor an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof.
 38. The method of claim 32, wherein thecompound is2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamideor an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof.
 39. The method of claim 32, wherein thecompound isN-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-fluorophenyl)acetamideor an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof.
 40. The method of claim 32, wherein thecompound is2-(2-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamideor an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof.
 41. The method of claim 32 wherein thecompound is(2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide)or an enantiomer or a mixture of enantiomers thereof, or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof.
 42. The method of claim 32, furthercomprising administering a therapeutically effective amount of a secondactive agent or a support care therapy.
 43. The method of claim 42,wherein the second active agent is a therapeutic antibody thatspecifically binds to a cancer antigen, a hematopoietic growth factor, acytokine, an anti-cancer agent, an antibiotic, a cox-2 inhibitor, animmunomodulatory agent, an immunosuppressive agent, a corticosteroid ora pharmacologically active mutant or derivative thereof.